WO2006074244A2 - Adamantyl derivatives as inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme - Google Patents

Adamantyl derivatives as inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme Download PDF

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Publication number
WO2006074244A2
WO2006074244A2 PCT/US2006/000210 US2006000210W WO2006074244A2 WO 2006074244 A2 WO2006074244 A2 WO 2006074244A2 US 2006000210 W US2006000210 W US 2006000210W WO 2006074244 A2 WO2006074244 A2 WO 2006074244A2
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WIPO (PCT)
Prior art keywords
amino
adamantane
hydrogen
methyl
alkyl
Prior art date
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PCT/US2006/000210
Other languages
French (fr)
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WO2006074244A3 (en
Inventor
Jyoti R. Patel
Qi Shuai
James T. Link
Jeffrey J. Rohde
Jurgen Dinges
Bryan K. Sorensen
Martin Winn
Hong Yong
Vince S. Yeh
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Abbott Laboratories
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Publication date
Priority to BRPI0606256-3A priority Critical patent/BRPI0606256A2/en
Priority to KR1020077017997A priority patent/KR101496190B1/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to MX2007008238A priority patent/MX2007008238A/en
Priority to ES06717418T priority patent/ES2386365T3/en
Priority to CA2594098A priority patent/CA2594098C/en
Priority to JP2007550440A priority patent/JP5078621B2/en
Priority to NZ555966A priority patent/NZ555966A/en
Priority to EP06717418A priority patent/EP1846363B1/en
Priority to AU2006204017A priority patent/AU2006204017B2/en
Priority to AT06717418T priority patent/ATE555081T1/en
Priority to KR1020137005468A priority patent/KR101496206B1/en
Publication of WO2006074244A2 publication Critical patent/WO2006074244A2/en
Publication of WO2006074244A3 publication Critical patent/WO2006074244A3/en
Priority to IL184328A priority patent/IL184328A/en
Priority to HK08104526.7A priority patent/HK1117138A1/en
Priority to IL213425A priority patent/IL213425A/en

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Definitions

  • the present invention relates to compounds that are inhibitors of the 11-beta- hydroxysteroid dehydrogenase Type 1 enzyme.
  • the present invention further relates to the use of inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions that are mediated by excessive glucocorticoid action.
  • Insulin is a hormone that modulates glucose and lipid metabolism. Impaired action of insulin (i.e., insulin resistance) results in reduced insulin-induced glucose uptake, oxidation and storage, reduced insulin-dependent suppression of fatty acid release from adipose tissue (i.e., lipolysis) and reduced insulin-mediated suppression of hepatic glucose production and secretion. Insulin resistance frequently occurs in diseases that lead to increased and premature morbidity and mortality.
  • Diabetes mellitus is characterized by an elevation of plasma glucose levels (hyperglycemia) in the fasting state or after administration of glucose during a glucose tolerance test. While this disease may be caused by several underlying factors, it is generally grouped into two categories, Type 1 and Type 2 diabetes.
  • Type 1 diabetes also referred to as Insulin Dependent Diabetes Mellitus (“IDDM”)
  • IDDM Insulin Dependent Diabetes Mellitus
  • type 2 diabetes also referred to as non-insulin dependent diabetes mellitus, or NIDDM
  • insulin resistance is a significant pathogenic factor in the development of hyperglycemia.
  • the insulin levels in type 2 diabetes patients are elevated (i.e., hyperinsulinemia), but this compensatory increase is not sufficient to overcome the insulin resistance.
  • Persistent or uncontrolled hyperglycemia in both type 1 and type 2 diabetes mellitus is associated with increased incidence of macrovascular and/or microvascular complications including atherosclerosis, coronary heart disease, peripheral vascular disease, stroke, nephropathy, neuropathy and retinopathy.
  • Insulin resistance is a component of the metabolic syndrome.
  • diagnostic criteria for metabolic syndrome have been established. To qualify a patient as having metabolic syndrome, three out of the five following criteria must be met: elevated blood pressure above 130/85 rnmHg, fasting blood glucose above 110 mg/dl, abdominal obesity above 40" (men) or 35" (women) waist circumference and blood lipid changes as defined by an increase in triglycerides above 150 mg/dl or decreased HDL cholesterol below 40 mg/dl (men) or 50 mg/dl (women). It is currently estimated that 50 million adults, in the US alone, fulfill these criteria. That population, whether or not they develop overt diabetes mellitus, are at increased risk of developing the macrovascular and microvascular complications of type 2 diabetes listed above.
  • Type 2 diabetes Available treatments for type 2 diabetes have recognized limitations. Diet and physical exercise can have profound beneficial effects in type 2 diabetes patients, but compliance is poor. Even in patients having good compliance, other forms of therapy may be required to further improve glucose and lipid metabolism.
  • One therapeutic strategy is to increase insulin levels to overcome insulin resistance. This may be achieved through direct injection of insulin or through stimulation of the endogenous insulin secretion in pancreatic beta cells.
  • Sulfonylureas e.g., tolbutamide and glipizide
  • meglitinide are examples of drugs that stimulate insulin secretion (i.e., insulin secretagogues) thereby increasing circulating insulin concentrations high enough to stimulate insulin-resistant tissue.
  • insulin and insulin secretagogues may lead to dangerously low glucose concentrations (i.e., hypoglycemia), hi addition, insulin secretagogues frequently lose therapeutic potency over time.
  • Alpha-glucosidase inhibitors e.g., acarbose
  • acarbose may delay carbohydrate absorption from the gut after meals, which may in turn lower blood glucose levels, particularly in the postprandial period.
  • these compounds may also cause gastrointestinal side effects.
  • Glitazones i.e., 5-benzylthiazolidine-2,4-diones
  • Glitazones are a newer class of compounds used in the treatment of type 2 diabetes. These agents may reduce insulin resistance in multiple tissues, thus lowering blood glucose. The risk of hypoglycemia may also be avoided.
  • Glitazones modify the activity of the Peroxisome Proliferator Activated Receptor ("PPAR") gamma subtype. PPAR is currently believed to be the primary therapeutic target for the main mechanism of action for the beneficial effects of these compounds.
  • Other modulators of the PPAR family of proteins are currently in development for the treatment of type 2 diabetes and/or dyslipidemia. Marketed glitazones suffer from side effects including bodyweight gain and peripheral edema.
  • GLP-I Glucagon-Like Peptide 1
  • DPP-IV Dipeptidyl Peptidase IV
  • GLP-I Glucagon-Like Peptide 1
  • DPP-IV Dipeptidyl Peptidase IV
  • Other examples include: Inhibitors of key enzymes involved in the hepatic glucose production and secretion (e.g., fructose- 1,6-bisphosphatase inhibitors) and direct modulation of enzymes involved in insulin signaling (e.g., Protein Tyrosine Phosphatase- IB, or "PTP-IB").
  • Another method of treating or prophylactically treating diabetes mellitus includes using inhibitors of 11- ⁇ -hydroxysteroid dehydrogenase Type 1 (1 l ⁇ -HSDl). Such methods are discussed in J.R. Seckl et al., Endocrinology, 142: 1371-1376, 2001 and references cited therein.
  • Glucocorticoids are steroid hormones that are potent regulators of glucose and lipid metabolism. Excessive glucocorticoid action may lead to insulin resistance, type 2 diabetes, dyslipidemia, increased abdominal obesity and hypertension. Glucocorticoids circulate in the blood in an active form (i.e., Cortisol in humans) and an inactive form (i.e., cortisone in humans).
  • 11 ⁇ -HSD 1 which is highly expressed in liver and adipose tissue, converts cortisone to Cortisol leading to higher local concentration of Cortisol. Inhibition of 1 l ⁇ -HSDl prevents or decreases the tissue specific amplification of glucocorticoid action thus imparting beneficial effects on blood pressure and glucose- and lipid-metabolism.
  • One aspect of the present invention is directed toward a compound of formula (I)
  • a 1 , A 2 , A 3 and A 4 are each individually selected from the group consisting of hydrogen, alkenyl, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cyano, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocyclesulfonyl, halogen, haloalkyl, -NR 5 -[C(R 6 R 7 )] n -C(O)-R 8 , -O-[C(R 9 R 10 )]p
  • R 18a and R 19a are each independently selected from the group consisting of hydrogen and alkyl; n is O or 1; p is O or l;
  • D is a member selected from the group consisting of a -O-, -S-, -S(O)- and -S(O) 2 -;
  • E is a member selected from the group consisting of alkyl, alkoxyalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, or R 4 and E taken together with the atoms to which they are attached form a heterocycle;
  • R 1 is a member selected from the group consisting of hydrogen and alkyl
  • R 2 is a member selected from the group consisting of hydrogen, alkyl and cycloalkyl
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl, or R 3 and R 4 taken together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
  • R 5 is a member selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen and. alkyl, or R 6 and R 7 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
  • R 8 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and -N(R 27 R 28 );
  • R 9 and R 10 are each independently selected from the group consisting of hydrogen and alkyl, or R 9 and R 10 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
  • R 11 is selected from the group consisting of hydroxy and -N(R 29 R 30 );
  • R is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
  • R 13 and R 14 are each independently selected from the group consisting of hydrogen, alkyl, alkylsufonyl, aryl, arylalkyl, aryloxyalkyl, arylsulfonyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealky
  • R 16 and R 17 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkylsufonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl, hydroxy, and - alkyl-C(O)N(R 201 R 202 ), or, R 16 and R 17 taken together with the atom to which they are attached form a heterocycle;
  • R 201 and R 202 are independently selected from the group consisting of hydrogen and alkyl;
  • R 18 , R 19 and R 20 are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl;
  • R 21 and R 22 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, cycloalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl and heterocyclesulfonyl;
  • R 23 and R 24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxy, alkylsulfonyl, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or, R 23 and R 24 taken together with the atom to which they are attached form a ring selected from the group consisting of heteroaryl and heterocycle;
  • R and R are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkylsufonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl, and hydroxy, or, R 25 and R 26 taken together with the atom to which they are attached form a heterocycle; R and R are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkylsufonyl, aryl, arylalkyl, aryloxy, ary
  • a further aspect of the present invention encompasses the use of the compounds of formula (T) for the treatment of disorders that are mediated by 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme, such as non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions that are mediated by excessive glucocorticoid action, comprising administering a therapeutically effective amount of a compound of formula (T).
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically suitable carrier.
  • a 2 , A 3 and A 4 are hydrogen
  • R 1 and R 2 are hydrogen; and A 1 , R 3 , R 4 , D and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (T), wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen;
  • R 3 and R 4 are hydrogen; and A 1 , D and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (T), wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen
  • R 3 and R 4 are hydrogen
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein
  • a 2 , A 3 and A 4 are hydrogen
  • R 1 and R 2 are hydrogen
  • R 3 and R 4 are hydrogen; D is -O-;
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen
  • R 3 and R 4 are hydrogen
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen; R 3 is hydrogen; R 4 is alkyl; and A 1 , D and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (J); wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen; R 3 is hydrogen;
  • R 4 is alkyl
  • D is -O-; and A 1 and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen; R 3 is hydrogen; R 4 is alkyl; D is -O-; E is as described in the summary of the invention.
  • a 1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR 12 , carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R 18 R 19 )-OR 20 , -C(O)- N(R 16 R 17 ), -C(R 183 R 1 ⁇ )-C(O)N(R 23 R 24 ), -C( ⁇ NOH)-N(H) 2 , -S(O) 2 -N(R 25 R 26 ), -CO 2 R 15 , -C(R 18a R 19a )-S(O) 2 -N(R 25 R 26 ), and -C(R 21 R 22 )-N(R 23 R 24 ) wherein R 12 , R 15 , R 16 , R 17 , R 18 , R 19 , R 18a , R 19a , R 21
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen; R 3 is hydrogen;
  • E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen;
  • R 3 and R 4 are alkyl; and A 1 , D and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen; R 3 and R 4 are alkyl; D is -O-; and A 1 and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen; R 3 and R 4 are alkyl;
  • a 2 , A 3 and A 4 are hydrogen
  • R 1 and R 2 are hydrogen; R 3 and R 4 are alkyl;
  • E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl. Another aspect of the present invention is directed toward a compound of formula (I), wherein
  • a 2 , A 3 and A 4 are hydrogen
  • R 1 and R 2 are hydrogen
  • R 3 and R 4 taken together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; and A 1 , D and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen;
  • R 3 and R 4 taken together with the atoms to which they are attached form a cycloalkyl ring; and A 1 , D and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen
  • R 3 and R 4 taken together with the atoms to which they are attached form a cycloalkyl ring
  • D is -O-; and A 1 and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen
  • R 3 and R 4 taken together with the atoms to which they are attached form a cycloalkyl ring
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein
  • a 2 , A 3 and A 4 are hydrogen
  • R 1 and R 2 are hydrogen; R 3 and R 4 taken together with the atoms to which they are attached form a cycloalkyl ring;
  • R 12 , R 15 , R 16 , R 17 , R 1S , R 19 , R 18a , R 19a , R 21 , R 22 , R 23 , R 24 , R 25 , and R 26 are as described in the summary of the invention.
  • E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen
  • R 3 and R 4 taken together with the atoms to which they are attached form a cyclopropyl ring; D is -O-;
  • E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein
  • a 2 , A 3 and A 4 are hydrogen
  • R 1 and R 2 are hydrogen
  • R 3 and R 4 taken together with the atoms to which they are attached form a cyclobutyl ring; D is -O-;
  • E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein
  • a 2 , A 3 and A 4 are hydrogen
  • R 1 and R 2 are hydrogen; and R 3 and R 4 taken together with the atoms to which they are attached form a heterocycle, and A 1 , D and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen
  • Another aspect of the present invention is directed toward a compound of formula (T), wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen;
  • E is as described in the summary of the invention.
  • D is -O-;
  • R 12 , R 15 , R 16 , R 17 , R 18 , R 19 , R 18a , R 19a , R 21 , R 22 , R 23 , R 24 , R 25 , and R 26 are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen
  • D is -O-;
  • E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein
  • a 2 , A 3 and A 4 are hydrogen
  • R 1 and R 2 are hydrogen; R 4 and E taken together with the atoms to which they are attached form a heterocycle; and A 1 and D are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (Tj, wherein
  • a 2 , A 3 and A 4 are hydrogen; R 1 and R 2 are hydrogen;
  • D is -O- and A 1 is as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen
  • a 1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR 12 , carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R 18 R 19 )-OR 20 , -C(O)- N(R 16 R 17 ), -C(R 18a R 19a )-C(O)N(R 23 R 24 ), -CeNOH)-N(H) 2 , -S(O) 2 -N(R 25 R 26 ), -CO 2 R 15 , -C(R 18a R 19a )-S(O) 2 -N(R 25 R 26 ), and -C(R 21 R 22 )-N(R 23 R 24 ) wherein R 12 , R 15 , R 16 , R 17 , R 18 , R 19 , R 18a , R 19a , R 21 ,
  • a 1 is selected from the group consisting of alkylsulfonyl, arylsulfonyl, cycloalkylsulfonyl, heteroarylsulfonyl and heterocyclesulfonyl;
  • a 2 , A 3 and A 4 are hydrogen; D is -O- ; and R 1 , R 2 , R 3 , R 4 , and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein A 1 is -S(O) 2 -N(R 25 R 26 ) wherein R 25 and R 26 are as described in the summary of the invention; A 2 , A 3 and A 4 are hydrogen;
  • D is -0-; and R 1 , R 2 , R 3 , R 4 , and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (T), wherein A 1 is -C(O)-N(R 16 R 17 ) wherein R 16 is selected from the group consisting of hydrogen and alkyl and R 17 is selected from the group consisting of arylalkyl and heteroarylalkyl; D is -0-;
  • a 2 , A 3 and A 4 are hydrogen; and R 1 , R 2 , R 3 , R 4 , and E are as described in the summary of the invention.
  • Another aspect of the present invention is directed toward a compound of formula (I), wherein A 2 , A 3 and A 4 are hydrogen;
  • R 1 and R 2 are hydrogen
  • R 12 , R 15 , R 16 , R 17 , R 18 , R 19 , R 18a , R 19a , R 21 , R 22 , R 23 , R 24 , R 25 , and R 26 are as described in the summary of the invention;
  • E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl; and R 3 and R 4 are each independently selected from the group consisting of hydrogen, alkyl and arylalkyl, or R 3 and R 4 together with the atom to which they are attached form a cycloalkyl ring.
  • Another aspect of the present invention is directed to a compound selected from the following group E-4-[(2-methyl-2-phenoxypropanoyl)amino]adamantane-l -carboxamide;
  • Another embodiment of the present invention discloses a method of inhibiting 11- beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
  • Another embodiment of the present invention discloses a method of treating disorders in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
  • Another embodiment of the present invention discloses a method of treating non- insulin dependent type 2 diabetes in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
  • Another embodiment of the present invention discloses a method of treating insulin resistance in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
  • Another embodiment of the present invention discloses a method of treating obesity in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula
  • Another embodiment of the present invention discloses a method of treating lipid disorders in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
  • Another embodiment of the present invention discloses a method of treating metabolic syndrome in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type
  • I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
  • Another embodiment of the present invention discloses a method of treating diseases and conditions that are mediated by excessive glucocorticoid action in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
  • Another embodiment of the present invention discloses a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) in combination with a pharmaceutically suitable carrier.
  • alkenyl refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
  • Alkenyls of the present invention can be uns ⁇ bstituted or substituted with one substituent selected from the group consisting of carboxy, alkoxycarbonyl and aryloxycarbonyl.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert- butoxy, pentyloxy and hexyloxy.
  • alkoxyalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl and methoxymethyl.
  • alkoxycarbonyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.
  • alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
  • alkylcarbonyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl- 1-oxopropyl, 1-oxobutyl and 1-oxopentyl.
  • alkylsulfonyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl.
  • alkyl-NH refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a nitrogen atom.
  • alkyl-NH-alkyl refers to an alkyl-NH group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • aryl as used herein, means a phenyl group, or a bicyclic or a tricyclic fused ring system.
  • Bicyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl group, as defined herein, or a heterocycle, as defined herein.
  • Tricyclic fused ring systems are exemplified by an aryl bicyclic fused ring system, as defined herein and fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl group, as defined herein, or a heterocycle, as defined herein.
  • Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl and tetrahydronaphthyl.
  • aryl groups of this invention maybe optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, aryl, arylalkoxy, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl, hydroxy, hydroxyalkyl, nitro, RjR 8 N-, R f R g Nalkyl, R f R g Ncarbonyl,
  • the substituent aryl, the aryl of arylalkoxy, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the substituent heteroaryl, the heteroaryl of heteroarylalkyl, the heteroaryl of heteroarylcarbonyl, the substituent heterocycle, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy, the heterocycle of heterocyclesulfonyl may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, R f R g N-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl
  • arylalkyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3- phenylpropyl and 2-naphth-2-ylethyl.
  • arylcarbonyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of arylcarbonyl include, but are not limited to, benzoyl and naphthoyl.
  • aryl-NH- refers to an aryl group, as defined herein, appended to the parent molecular moiety through a nitrogen atom.
  • aryl-NH-alkyl refers to an aryl-NH- group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • arylalkoxy refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy moiety, as defined herein.
  • aryloxy refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • aryloxy include, but are not limited to phenoxy, naphthyloxy, 3- bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy and 3,5-dimethoxyphenoxy.
  • aryloxyalkyl refers to an aryloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • aryloxycarbonyl refers to an aryloxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • arylsulfonyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of arylsulfonyl include, but are not limited to, phenylsulfonyl, 4- bromophenylsulfonyl and naphthylsulfonyl.
  • carbonyl refers to a -C(O)- group.
  • Carboxyalkyl refers to a carboxy group as defined herein, appended to the parent molecular moiety through an alkyl group as defined herein.
  • carboxycycloalkyl refers to a carboxy group as defined herein, appended to the parent molecular moiety through an cycloalkyl group as defined herein.
  • cycloalkyl refers to a monocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms.
  • Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Bicyclic fused ring systems are exemplified by a cycloalkyl group appended to the parent molecular moiety and fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl group, as defined herein, or a heterocycle, as defined herein.
  • Tricyclic fused ring systems are exemplified by a cycloalkyl bicyclic fused ring system, as defined herein and fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl group, as defined herein, or a heterocycle, as defined herein.
  • Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms.
  • bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane.
  • Tricyclic ring systems are also exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms.
  • tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.0 3>7 ]nonane andtricyclo[3.3.1.1 3 ' 7 ]decane (adamantane).
  • the cycloalkyl groups of this invention may be substituted with 1 , 2, 3, 4 or 5 s ⁇ bstituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heteroarylcarbonyl
  • the substituent aryl, the aryl of arylalkyl, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the substituent heteroaryl, the heteroaryl of heteroarylalkyl, the heteroaryl of heteroarylcarbonyl, the substituent heterocycle, the heterocycle of heterocyclealkyl, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy, the heterocycle of heterocyclesulfonyl maybe optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, R f R g N-, R f R g Nalkyl, R f R g Ncarbon
  • cycloalkylalkyl refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4- cycloheptylbutyl.
  • cycloalkylcarbonyl refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl and cyclohexylcarbonyl.
  • cycloalkyloxy refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein.
  • cycloalkylsulfonyl refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of cycloalkylsulfonyl include, but are not limited to, cyclohexylsulfonyl and cyclobutylsulfonyl.
  • halo refers to -Cl, -Br, -I or -F.
  • haloalkyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2- fluoroethyl, trifluoromethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl.
  • haloalkylcarbonyl refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • heteroaryl refers to an aromatic monocyclic ring or an aromatic bicyclic ring system.
  • the aromatic monocyclic rings are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S.
  • the five membered aromatic monocyclic rings have two double bonds and the six membered aromatic monocyclic rings have three double bonds.
  • the bicyclic heteroaryl groups are exemplified by a monocyclic heteroaryl ring appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
  • heteroaryl include, but are not limited to, benzimidazolyl,_benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indazolyl, indolyl, indolizinyl, isobenzofuranyl, isoindolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl.
  • heteroarylalkyl refers to a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • the heteroaryls of this invention may be optionally substituted with 1, 2 or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, hydroxy
  • the substituent aryl, the aryl of arylalkyl, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the substituent heteroaryl, the heteroaryl of heteroarylalkyl, the substituent heterocycle, the heterocycle of heterocyclealkyl, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, R f R g N-, R f R g Nalkyl, R f R g Ncarbonyl and R f R g Nsulfonyl wherein R f and Rg are
  • heterocycle refers to a non-aromatic monocyclic ring or a non-aromatic bicyclic ring.
  • the non-aromatic monocyclic ring is a three, four, five, six, seven, or eight membered ring containing at least one heteroatom, independently selected from the group consisting of N, O and S.
  • monocyclic ring systems include, but are not limited to, azetidinyl, aziridinyl, diazepinyl, dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydrothienyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1- dioxido
  • bicyclic heterocycles are exemplified by a monocyclic heterocycle appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
  • Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent atoms of the monocyclic ring are linked by a bridge of between one and three additional atoms selected from the group consisting o f carbon, nitrogen and oxygen.
  • bicyclic ring systems include but are not limited to, for example, benzopyranyl, benzothiopyranyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, 1,5- diazocanyl, 3,9-diaza-bicyclo[4.2.1]non-9-yl, 3,7-diazabicyclo[3.3.1]nonane, octahydro- pyrrolo[3,4-c]pyrrole, indolinyl, isoindolinyl, 2,3,4,5-tetrahydro-lH-benzo[c]azepine, 2,3,4,5-tetrahydro-lH-benzo[ ⁇ ]azepine, 2,3,4,5-tetrahydro-lH-benzo[d]azepine, tetrahydroisoquinolinyl and tetrahydroquinolinyl.
  • the heterocycles of this invention may be optionally substituted with 1, 2 or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro, R f R g N-, R f RgNalkyl, R f RgNcarbonyl and R f RgNsulfonyl, wherein R f and R
  • the substituent aryl, the aryl of arylalkyl, the aryl of arylcarbonyl, the aryi of aryloxy, the aryl of arylsulfonyl, the heteroaryl, the heteroaryl of heteroarylalkyl, the substituent heterocycle, the heterocycle of heterocyclealkyl, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy, may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, R f R g N-, RfRgNalkyl, R f R g Ncarbonyl and R f R g Nsulfonyl wherein R f and R g are as described
  • heterocyclealkyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heterocyclealkyl include, but are not limited to, pyridin-3- ylmethyl and 2-pyrimidin-2-ylpropyl.
  • heterocyclealkoxy refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • heterocycleoxy refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein.
  • heterocycleoxyalkyl refers to a heterocycleoxy, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heterocycle-NH- refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a nitrogen atom.
  • heterocycle-NH-alkyl refers to a heterocycle-NH-, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • heterocyclecarbonyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of heterocyclecarbonyl include, but are not limited to, 1- piperidinylcarbonyl, 4-morpholinylcarbonyl, pyridin-3-ylcarbonyl and quinolin-3-ylcarbonyl.
  • heterocyclesulfonyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of heterocyclesulfonyl include, but are not limited to, 1- piperidinylsulfonyl, 4-morpholinylsulfonyl, pyridin-3-ylsulfonyl and quinolin-3-ylsulfonyl.
  • hydroxy refers to an -OH group.
  • hydroxyalkyl refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • hydroxyalkyl include, but are not limited to, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl and 2-ethyl-4-hydroxyheptyl.
  • oxy refers to a -O- group.
  • sulfonyl refers to a -S(O) 2 - group.
  • the present compounds may exist as therapeutically suitable salts.
  • the term "therapeutically suitable salt,” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation and allergic response, commensurate with a reasonable benefit/risk ratio and effective for their intended use.
  • the salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid.
  • a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid.
  • the resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure.
  • salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, form ate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifiuoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydroch
  • the amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.
  • Basic addition salts may be prepared during the final isolation and purification of the present compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine.
  • the present compounds may also exist as therapeutically suitable prodrugs.
  • therapeutically suitable prodrug refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation and allergic response, are commensurate with a reasonable benefit/risk ratio and are effective for their intended use.
  • prodrug refers to compounds that are rapidly transformed in vivo to the parent compounds of formula (I-IXc) for example, by hydrolysis in blood.
  • prodrug refers to compounds that contain, but are not limited to, substituents known as “therapeutically suitable esters.”
  • therapeuticically suitable ester refers to alkoxycarbonyl groups appended to the parent molecule on an available carbon atom.
  • a "therapeutically suitable ester” refers to alkoxycarbonyl groups appended to the parent molecule on one or more available aryl, cycloalkyl and/or heterocycle groups as defined herein.
  • Compounds containing therapeutically suitable esters are an example, but are not intended to limit the scope of compounds considered to be prodrugs.
  • prodrug ester groups include pivaloyloxymethyL acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art.
  • Other examples of prodrug ester groups are found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • Asymmetric centers may exist in the present compounds.
  • Individual stereoisomers of the compounds are prepared by synthesis from chiral starting materials or by preparation of racemic mixtures and separation by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns.
  • Starting materials of particular stereochemistry are either commercially available or are made by the methods described hereinbelow and resolved by techniques well known in the art.
  • Geometric isomers may exist in the present compounds.
  • the invention contemplates the various geometric isomers and mixtures thereof resulting from the disposal of substituents around a carbon-carbon double bond, a cycloalkyl group, or a heterocycloalkyl group. Substituents around a carbon-carbon double bond are designated as being of Z or E configuration and substituents around a cycloalkyl or heterocycloalkyl are designated as being of cis or trans configuration.
  • the invention contemplates the various isomers and mixtures thereof resulting from the disposal of substituents around an adamantane ring system.
  • Substituted adamantanes of general formula (3), wherein A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , D and E are as defined in formula I, may be prepared as in Scheme 1.
  • Substituted adamantamines of general formula (1) may be treated with acylating agents of general formula (4), wherein X is chloro, bromo, or fluoro, Y is a leaving group such as Br (or a protected or masked leaving group) to provide amides of general formula (5).
  • the substituted amides of general formula (5) may be treated with nucleophiles of general formula (6), wherein J is oxygen or sulfur and a base such as sodium hydride. When J is sulfur that reaction may be followed by oxidation with reagents like Oxone to provide amides of general formula (3) wherein D can become S(O) or S(O) 2 .
  • a , A 2 , A 3 and/or A 4 in amines of formula (1) may exist as a group further substituted with a protecting group such as a carboxylic acid protected as the methyl ester. Examples containing a protected functional group may be required due to the synthetic schemes and the reactivity of said groups and could be later removed to provide the desired compound. Such protecting groups can be removed using methodology known to those skilled in the art or as described in T. W. Greene, P. G. M. Wuts "Protective Groups in Organic Synthesis” 3 rd ed. 1999, Wiley & Sons, Inc.
  • Substituted adamantane amines of general formula (8) wherein A 1 , A 2 , A 3 , A 4 , R 1 and R 2 are as defined in formula I, may be prepared as in Scheme 2.
  • Substituted adamantane ketones of general formula (7) can be purchased or prepared using methodology known to those in the art. Ketones of general formula (7) can be treated with ammonia or primary amines (R 2 NH 2 ) followed by reduction with reagents such as sodium borohydride or H 2 over Pd/C in a solvent like methanol to provide amines of general formula (8).
  • a 1 , A 2 , A 3 and/or A 4 in ketones of formula (7) may be a functional group substituted with a protecting group such as a carboxylic acid protected as the methyl ester.
  • protecting groups can be removed using methodology known to those in the art in amines of general formula (8) or in compounds subsequently prepared from ketones of general formula (7) or amines of general formula (8).
  • Substituted adamantanes of general formula (10), wherein A 2 , A 3 and A 4 are as defined in formula I, may be prepared as in Scheme 3.
  • Substituted adamantanes of general formula (9) can be purchased or prepared using methodology known to those skilled in the art.
  • Adamantanes of general formula (9) can be treated with oleum and formic acid followed by an alcohol GOH, where G is an alkyl, cycloalkyl, hydrogen, aryl, or acid protecting group, to provide adamantanes of general formula (10).
  • G in formula (10) may be a protecting group such as methyl.
  • Substituted adamantanes of general formula (14), wherein A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , D, E, R 16 and R 17 are as defined in formula I, may be prepared as in Scheme 4.
  • Adamantyl acids of general formula (11) may be prepared as described herein or using methodology known to those skilled in the art.
  • the acids of general formula (11) may be coupled with amines of general formula (12), wherein R 16 and R 17 are defined as in formula I, with reagents such as O-(benzotrialzol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU) to provide amides of general formula (13).
  • TBTU O-(benzotrialzol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate
  • a 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 16 and R 17 in amines of formula (13) may contain a functional group substituted with a protecting group, for example, a carboxy protected as an ester. These protecting groups may be removed using methodology known to those in the art to provide amides of general formula (14).
  • Acids of general formulas (17) wherein R 3 , R 4 , D and E are as defined in formula (I) can be prepared as shown in Scheme 5.
  • Phenols and thiols of general formula (15) wherein D is -O- or -S- purchased or prepared using methodology known to those skilled in the art, may be treated with a reagent like l,l,l-trichloro-2-methyl-propan-2-ol (16) in the presence of abase like sodium hydroxide in a solvent like acetone to provide acids of general formula (17).
  • Removal of the acid protecting group, P provides acids of formula (17). Cleavage of the acid protecting group can be conducted by either acidic or basic hydrolysis when P is C 1 -C 6 alkyl, or hydrogenolyis when P is benzyl.
  • esters of general formula (18) may be coupled with halides of formula E-X 1 wherein X 1 is Cl, Br or I and E is aryl or heteroaryl, under with a metal catalyst like palladium along with ligands, to provide compounds of formula (19).
  • Adamantane acids of general formula (20) can be coupled with amines of formula R f R g NH, in the presence of a coupling agent such as, but not limited to, TBTU, and a base such as, but not limited, to diisopropylethylamine.
  • the reaction is generally performed in a solvent such as, but not limited to, DMF, at a temperature of about room temperature to about 50 0 C to provide amides of general formula (21).
  • Adamantanes of general formula (22) wherein P is hydrogen or an acid protecting group such as, but not limited to, C 1 -C 6 alkyl, aryl (substituted or unsubstituted) or arylalkyl (substituted or unsubstituted), can be converted to aldehydes of formula (23) by (a) treatment with a reducing agent such as, but not limited to, lithium aluminum hydride, in a solvent like THF; and (b) treating the product from step (a) with an oxiding agent such as, but not limited to, TPAP, in the presence of NMO, and in a solvent like dichloroethane.
  • a reducing agent such as, but not limited to, lithium aluminum hydride, in a solvent like THF
  • an oxiding agent such as, but not limited to, TPAP, in the presence of NMO, and in a solvent like dichloroethane.
  • Adamantane aldehydes of general formula (23) can be treated with TosMIC and a base like t-BuOK in a solvent mixture like DME and ethanol to provide nitriles of general formula (24).
  • Nitriles of general formula (24) can be hydrolyzed with potassium hydroxide in a solvent like ethylene glycol to provide acids of general formula (25).
  • nitriles of general formula (24) can be transformed to amides of formula (26).
  • Tetrazoles of formula (27) can be prepared from adamantanes of general formula (24) when treated with reagents like sodium azide and zinc bromide in a solvent like water and isopropanol.
  • Substituted adamantanes of general formula (28) can be dehydrated with a reagent like TBTU in the presence of a base like isopropylethylamine in a solvent like N,N- dimethylacetamide to provide nitriles of general formula (29).
  • Nitriles of general formula (29) can be treated with reagents like trimethyl tin chloride and sodium azide in a solvent like toluene to provide tetrazoles of general formula (30).
  • adamantane amines of general formula (31) wherein P is hydrogen or C 1 -C 6 alkyl can be (a) treated with a reagent like CbzCl in a solvent like dichloromethane in the presence of a base like diisopropylethylamine; (b) treating the resulting product with a reagent like KOTMS in a solvent like THF; and (c) treating the acid from step (b) with ammonia or ammonium hydroxide in the presence of a reagent like EDCI and HOBt, and a base like diisopropylethylamine, in a solvent like DMF, to yield adamantane amides of general formula (32) wherein P is a protecting group like -C(O)OCH 2 C 6 Hs.
  • the amides of general formula (32) can be (a) treated with a reagent like trifluoroacetic anhydride in a solvent like dichloromethane in the presence of a base like triethylamine; and (b) treating the intermediate from step (a) with a catalyst like Pd(OH) 2 on carbon under an atmosphere of hydrogen, to provide amines of formula (33).
  • Amines of general formula (33) can be coupled to acids of general formula (17), in the presence of a reagent like HATU and a base like diisopropylethylamine, in a solvent like DMF, to provide compounds of general formula (29).
  • Substituted adamantanes of general formula (34), wherein A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , D and E are as defined in formula I, can be prepared from treatment of compounds of formula (29) with hydroxylamine hydrochloride in a solvent like DMSO, in the presence of a base like diisopropylethylamine.
  • Substituted adamantanes of general formula (37) and (38), wherein A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , D and E are as defined in formula I, and R 101 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle, can be prepared as shown in Scheme 10.
  • Substituted adamantanes of general formula (35) can be (a) treated with trifluoroacetic anhydride in a solvent like trifluoroacetic acid; and (b) treating the product of step (a) with a thiol of formula R 101 SH at elevated temperature, typically at about 120 0 C for a period of about 20 hours, in a solvent like trifluoroacetic acid to provide thioethers of general formula (36).
  • Thioethers of general formula (36) can be oxidized with an oxidizing agent such as, but not limited to, 3-chloroperbenzoic acid, in a solvent such as, but not limited to, dichloromethane, to provide sulfoxides of general formula (37) and/or sulfones of general formula (38).
  • an oxidizing agent such as, but not limited to, 3-chloroperbenzoic acid
  • a solvent such as, but not limited to, dichloromethane
  • Substituted adamantanes of general formula (22) wherein P is hydrogen or an acid protecting group such as, but not limited to, C 1 -C 6 alkyl, aryl (substituted or unsubstituted) or arylalkyl (substituted or unsubstituted), can be converted alcohols of formula (39) by treatment with a reducing agent such as, but not limited to, lithium aluminum hydride or diisobutylaluminum hydride in a solvent like THF. Reaction of the alcohols of general formula (39) with trifluoromethanesulfonic anhydride in the presence of a base like pyridine and in a solvent like dichloromethane provides the intermediate triflate that can be isolated.
  • a reducing agent such as, but not limited to, lithium aluminum hydride or diisobutylaluminum hydride in a solvent like THF.
  • Sulfonic acids of general formula (41) can be coupled with an amine of formula R 25 R 26 NH wherein R 25 and R 26 are defined as in formula I to provide compounds of formula (42).
  • Numerous reaction conditions for such a conversion are known to one skilled in the art.
  • One such coupling utilizes triphosgene in the presence of a base like triethylarnine with a catalytic amount of dimethylformamide in a solvent like dichloromethane, followed by the addition an amine of formula R 25 R 26 NH.
  • the mono alkylation can be facilitated with an alkylating reagent of formula R 25 X 1 wherein R 25 is methyl, benzyl, and allyl, and X 1 is a leaving group such as, but not limited to, Cl, Br, I, triflate or tosylate.
  • the reaction is generally conducted in the presence of a base such as, but not limited to, alkali metal carbonates (for example, cesium carbonate and the like), in a solvent such as, but not limited to, DMF, providing compounds of formula (42) wherein R 25 is methyl, benzyl, and allyl, and R 26 is hydrogen.
  • compounds of formula (42) wherein R and R are identical and are as defined in formula (I) other than hydrogen can be prepared from the reaction of compounds of formula (42) wherein R 25 and R 26 are hydrogen and about two equivalents of the alkylating agent.
  • Substituted adamantanes of general formula (46), wherein A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , R 16 , R 17 , D and E are as defined in formula (I) can be prepared as shown in Scheme 12.
  • Substituted adamantanes of general formula (43) can be carbonylated with formic acid and oleum and poured into a solution of formula R 15 OH to provide an adamantane of general formula (44) wherein R 15 is as defined in formula (I).
  • Adamantanes of general formula (44) wherein R 15 is not hydrogen can be converted to admantanes of formula (44) wherein R 15 is hydrogen using methodologies listed in T. W.
  • Adamantanes of general formula (45) may be treated with alcohols or thiols of general formula (15) wherein D is — O- or — S— and E is defined as in formula (I), in the presence of a base like potassium carbonate in a solvent like toluene to provide adamantanes of general formula (46).
  • Adamantanes of general formula (46) wherein D is -S- can be converted to compounds of formula (46) wherein D is -S(O)- or -S(O) 2 - by reacting with an oxidizing agent such as, but not limited to, oxone in a solvent like methanol.
  • an oxidizing agent such as, but not limited to, oxone in a solvent like methanol.
  • Substituted adamantanes of general formula (47) can be brominated with a reagent like hydrobromic acid in a solvent like water to provide bromides of general formula (48).
  • Adamantanes of general formula (48) when treated with ethylene glycol and a catalytic amount of an acid like p-toluenesulfonic acid in a solvent like benzene provide adamantanes of general formula (49).
  • Bromides of general formula (49) can be (a) treated with Rieke zinc in a solvent like tetrahydrofuran; and (b) followed by treatment with reagent (50) (prepared as described in Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q.
  • Adamantanes of general formula (51) may be treated with lithium amide of formula LiNHR 25 R 26 (prepared in situ by reacting ammonia with lithium or amines of formula R 25 R 26 NH wherein R 25 and R 26 are other than hydrogen, with t-butyl lithium) in a solvent mixture like ammonia and tetrahydrofuran.
  • the resulting sulfanamides can be oxidized with a reagent like osmium tetroxide with a catalyst oxidant like NMO in a solvent like tetrahydrofuran to provide sulfonamides of general formula (52).
  • Adamantanes of general formula (52) can be deketalized with reagents like hydrochloric acid in a solvent like water and tetrahydrofuran to provide ketones of formula (53).
  • Ketones of formula (53) can be treated with amines of formula R 25 R 26 NH followed by reduction with reducing reagents such as, but not limited to, sodium borohydride or hydrogen over Pd/C in a solvent like methanol to provide amines of general formula (54).
  • Substituted adamantanes of general formula (55), (56) and (57) wherein R is hydrogen, alkyl or aryl, and A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , R 23 , R 24 , D and E are as defined in formula (I), can be prepared as shown in Scheme 14.
  • Substituted adamantanes of general formula (23) can be treated with reagents like ammonia and glyoxal in a solvent like water to provide imidazoles of general formula (55).
  • Reaction of compounds of formula (23) with Wittig reagent such as, but not limited to, triethyl phosphonoacetate and a base like sodium hydride in a solvent like dimethoxyethane provides esters of general formula (56) wherein R 102 is alkyl or aryl.
  • Esters of general formula (56) can be cleaved with lithium hydroxide in a solvent mixture like tetrahydrofuran and water to provide acids of general formula (56) wherein R 102 is hydrogen.
  • Adamantanes of general formula (23) can be reductively animated with amines of general formula R 23 R 24 NH with a reagent like sodium triacetoxyborohydride in the presence of an acid like acetic acid in a solvent like dichloroethane to yield amines of general formula (57).
  • Substituted adamantanes of general formula (60), wherein A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , D and E are as defined in formula I and Q is hydrogen, alkyl, or cycloalkyl, can be prepared as shown in Scheme 15.
  • Substituted adamantanes of general formula (23) can be treated with a reagent like acetylenemagnesium chloride in a solvent like THF to yield alcohols of general formula (58).
  • Adamantane alcohols of general formula (58) can be oxidized with a reagent like Dess- Martin periodinane in a solvent like dichloromethane to provide alkynones of general formula (59).
  • Alkynones of general formula (59) can be reacted with a reagent like hydroxylamine hydrochloride in the presence of a base like potassium carbonate in a solvent like isopropanol to provide heterocycles of general formula (60).
  • Adamantanes of general formula (39) can be alkylated with a reagent of formula R 20 X 1 , wherein X 1 is a halide or other leaving group like bromide, iodide, tosylate or triflate, in the presence of a base like sodium hydride in a solvent like dimethylformamide to yield ethers of general formula (61).
  • a 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , and D are as defined in formula (I) and R 103 and R 104 are alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocycle, heteroaryl, heteroarylalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or heterocyclealkyl, or R 103 and R 104 combined to the atom to which they are attached form a heterocycle or heteroaryl can be prepared as shown in Scheme 17.
  • Substituted adamantanes of general formula (62) wherein X 1 is a halide or triflate can be coupled with amines of formula IStHR 103 R 10 with a reagent combination like copper iodide and N,N-dimethylglycine in a solvent like DMSO under microwave heating to provide adamantanes of general formula (63).
  • Adamantanes of general formula (64) can be halogenated with a reagent like N- bromosuccinimde in the presence of an acid like HBr in a solvent like dichloromethane to yield aryl halides of general formula (65).
  • the isomers were separated by column chromatography (silica gel, 5-35% acetone in hexane) to furnish 0.78 g of E-2-bromo-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide and 0.39 g of Z-2-bromo-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide.
  • E-4-(2-bromo-2-methyl-propionylamino)-adamantane-l-carboxylic acid methyl ester A solution of E- 2-bromo-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide (0.78 g, 2.48mmol) in 99% formic acid (2.5 mL) was added dropwise with vigorous gas evolution over 10 minutes to a rapidly stirred 30% oleum solution (7.5 mL) heated to 60 0 C (W. J. Ie Noble, S. Srivastava, C. K. Cheung, J. Org. Chem. 48: 1099-1101, 1983).
  • Step B The methyl ester of the title compound obtained from step A was hydrolyzed with 2N aqueous NaOH, THF and ethanol (2:1:1, 2 mL) at room temperature overnight.
  • the reaction mixture was acidified with IN HCl and extracted with ethyl acetate.
  • the organic layer was separated, washed with water and brine respectively, dried (MgSO 4 ) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound.
  • E-4-(2-methyl-2-phenoxy-propionylaminoy adamantane- 1 -carboxylic acid amide A solution of E-4-(2-methyl-2-phenoxy-propionylamino)-adamantane-l -carboxylic acid (23 mg, 0.064 mmoles) in DCM (2 mL) was treated with HOBt (9.5 mg, 0.07 mmoles) and ⁇ DCI (14.7 mg, 0.077 mmoles) and stirred at room temperature for 1 hour. Excess of aqueous (30%) ammonia (2 mL) was added and the reaction was stirred for additional 20 hours.
  • E-4-[2-methyl-2-(2-methyl-cyclohexyloxyVpropionylamino]-adamantane-l-carboxylic acid methyl ester 71.6 mg, 0.2 mmoles
  • 2-methylcyclohexanol 0.033 mL, 0.24 mmoles
  • tetrabutylammonium bromide 6 mg, 0.02 mmoles
  • reaction mixture was diluted with DCM, neutralized with 3N HCl and layers separated. Organic layer was washed with water (3x2 mL), dried (MgSO 4 ) and filtered. The filtrate was concentrated under reduced pressure to provide crude methyl ester of the title compound that was purified on reverse phase HPLC and hydrolyzed with 2N aqueous NaOH, THF and ethanol (2:1:1, 2 mL) at room temperature for 20 hours. The reaction mixture was acidified with IN HCl and extracted with ethyl acetate. The organic layer was separated, washed with water and brine respectively, dried (MgSO 4 ) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound.
  • Example 7B E-4-Amino-adamantane-l-carboxylic acid methyl ester Methanol (85 mL) was cooled to 0 0 C; acetyl chloride (15.5 mL) was added dropwise; and then the solution was warmed to 23 0 C for 15-20 minutes.
  • E-4-[2-(4-chloro-phenoxy)-2-methyl-propionylamino]-adamantane-l-carboxylic acid To the solution of E-4-Adamantamine -1-carboxylic acid methyl ester (49 mg, 0.2 mmoles) and triethylamine (0.097 mL, 0.7 mmoles) in DCM (1.0 mL) was added a solution of 2-(4-chlorophenoxy)-2-methylpropionyl chloride (55 mg, 0.24 mmoles) in DCM (1.0 mL). The resulting reaction mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure. The residue was partitioned between ethylacetate and water.
  • the organic layer was separated and washed with IN HCl, water and brine, dried (MgSO4) and filtered.
  • the filtrate was concentrated under reduced pressure to provide the crude methyl ester of the title compound that was purified on reverse phase HPLC and hydrolyzed with 2N aqueous NaOH, THF and ethanol (2:1:1, 2 mL) at room temperature for 20 hours.
  • the reaction mixture was acidified with IN HCl and extracted with ethyl acetate.
  • the organic layer was separated, washed with water and brine respectively, dried (MgSO 4 ) and filtered.
  • the filtrate was concentrated under reduced pressure to provide the title compound.
  • the filtrate was concentrated under reduced pressure to provide the crude compound that was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of 40mL/min. to provide the title compound.
  • Example 21 A was prepared according to the procedure outlined in Example ID, substituting 3-chlorophenol for phenol.
  • Example 22A was prepared according to the procedure outlined in Example ID, substituting 4-trifluoromethoxyphenol for phenol.
  • Example IE The title compound was prepared using the procedure as described in Example IE, substituting the product of Example 22A for the product of Example ID.
  • the crude acid product was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (40mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 12min (15min run time) at a flow rate of 70mL/min.to provide the title compound.
  • reaction mixture was allowed to come to room temperature. Before last addition of sodium hydroxide, acetone (2 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 48 hours and concentrated in vacuo.
  • the residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of 40mL/min. and hydrolyzed as described in step B of Example ID to provide the title compound.
  • Example 26A was prepared according to the procedure outlined in Example 25A, substituting (4-hydroxy-phenyl)-carbamic acid tert-butyl ester for 2,3-dimethylphenol.
  • Example 26B was prepared using the procedure as described in Example 25B, substituting the product of Example 26A for the product of Example 25 A.
  • Example 28A was prepared according to the procedure outlined in Example 24, substituting glycine methyl ester hydrochloride for 4-aminomethyl-benzoic acid methyl ester hydrochloride.
  • Step A The product of Step A (1.56 g, 5.71 mmol) was dissolved in THF (30 mL) and KOTMS (1.1 g, 8.57 mmol) was added in one portion. The resulting solution was stirred at room temperature overnight. Et 2 O (30 mL) and water (40 mL) were added to the reaction to partition the mixture. The phases were separated, and the aqueous phase was acidified using 10% NaHSO 4 solution and extracted with EtOAc. The combined organic phases were dried over MgSO 4 , filtered and concentrated to give the title compound as a white solid.
  • HATU (2.46 g, 6.48 mmol) was added in one portion to a solution of the product of Step B of Example 3OA (1.40 g, 5.40 mmol), the product of Example 7B (1.45 g, 5.95 mmol), and DIPEA (2.82 mL, 16.2 mmol) in dry CH 2 Cl 2 (20 mL).
  • the resulting solution was allowed to stir at room temperature overnight before it was diluted with CH 2 Cl 2 and washed with aqueous NaHSO 4 solution, 1 M NaOH, dried (Na 2 SO 4 ) and evaporated. The residue was purified over silica gel using 30% EtOAc / hexanes and concentrated to give an oil.
  • Step A To the product of Step A (2.27 g, 5.04 mmol) in THF (15 mL) was added KOTMS (1.42 g, 11.08 mmol) and the resulting solution was stirred at room temperature overnight before it was diluted with Et 2 O and water. The phases were separated and the aqueous phase was acidified with NaHSO 4 solution and extracted with EtOAc. The combined organic phases were dried (MgSO 4 ) and evaporated to give a white solid.
  • Step C To the product of Step A (2.27 g, 5.04 mmol) in THF (15 mL) was added KOTMS (1.42 g, 11.08 mmol) and the resulting solution was stirred at room temperature overnight before it was diluted with Et 2 O and water. The phases were separated and the aqueous phase was acidified with NaHSO 4 solution and extracted with EtOAc. The combined organic phases were dried (MgSO 4 ) and evaporated to give a white solid.
  • EDCI (1.40 g, 7.25 mmol) was added to a solution of the product of Step B (2.17 g, 4.84 mmol), HOBt (1.17 g, 8.71 mmol), DIPEA (2.5 mL, 14.4 mmol) in dry CH 2 Cl 2 (20 mL). The resulting solution was allowed to stir at room temperature for 1 hr before NH 3 solution was added (12 mL, 2M in iPrOH). The mixture was stirred for 2 hours at 25 0 C, diluted with CH 2 Cl 2 and washed with NaHSO 4 solution, IM NaOH, brine, dried (Na 2 SO 4 ) and evaporated.
  • Example 31 A was prepared according to the procedure outlined in Example 25 A, substituting 2-hydroxy-benzonitrile for 2,3-dimethylphenol.
  • Example 3 IB was prepared using the procedure as described in Example 25B, substituting the product of Example 31A for the product of Example 25A.
  • Example 32 A was prepared according to the procedure outlined in Example 25 A, substituting 4-benzyloxy-phenol for 2,3-dimethylphenol.
  • Example 32B was prepared according to the procedure outlined in Example 25B, substituting the product of Example 32A for the product of Example 25 A.
  • Example 32C was prepared according to the procedure outlined in Example IE, substituting the product of Example 32B for the product of Example ID.
  • Example 32C The product of Example 32C (62 mg, 0.13 mmol) was debenzylated using 20% Pd(OH) 2 /C (63 mg) and methanol (2mL) at 60 psi at room temperature for 20 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide the crude product that was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of 40mL/min. to provide title compound as a white solid.
  • Example 33A To a solution of the product of Example 33A (990 mg, 2.63 mmol) in DCE (8.0 mL) were added NMO (461 mg, 3.94 mmol), TPAP (46 mg, 0.13 mmol) and molecular sieves at room temperature under N 2 flow. The reaction mixture was stirred overnight at room temperature. It was filtered through Celite and washed with DCM 3 times. The combined filtrate was concentrated under reduced pressure and purified by flash chromatography with 30% ethyl acetate / 70% hexane to provide the title compound (740 mg, 75%).
  • Example 33D r(E)-4-([2-(4-Chlorophenoxy)-2-methylpropanovnammo
  • Example 33C To a solution of the product of Example 33C (22 mg, 0.057 mmol) in MeOH (0.15 ml) / DMSO (0.005 ml) were added 30% H 2 O 2 (0.011 ml) and 0.2 M NaOH (0.006 ml). The reaction mixture was heated to 5O 0 C overnight and concentrated. The residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of 40mL/min. to provide the title compound (13 mg, 56%).
  • Example 33C To a solution of the product of Example 33C (65 mg, 0.168 mmol) in water (0.2 ml) / isopropanol (0.1 ml) were added NaN 3 (22 mg, 0.337 mmol) and ZnBr 2 (19 mg, 0.084 mmol). The reaction mixture was heated to 15O 0 C in a sealed tube for two days and concentrated. The residue was purified by reverse phase preparative HPLC on a Waters
  • the crude reaction mixture was diluted with EtOAc, washed with water (3x) and brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • the crude product was purified by silica gel chromatography employing a solvent gradient (hexane ⁇ 60:40 hexane:EtOAc) to yield the title compound(0.74 g, 90%) as a white solid.
  • Example 36B N- ⁇ (E)-5-r(Sulfonic acid)methyl1-2-adamantyl ⁇ -2-(4-chlorophenoxyV2-methylpropananiide
  • acetic acid 10 niL
  • 30% hydrogen peroxide in water 1.6 niL, 15.3 mmol
  • the reaction solution was stirred at room temperature overnight and excess peroxide quenched by adding dimethylsulf ⁇ de (1.9 mL, 25.5 mmol) and stirring for 2 h.
  • the reaction solution was concentrated under reduced pressure to provide the crude product as a white solid.
  • step A The product of step A (6.49 g, 18.91 mmol) was dissolved in dry THF (90 mL) and KOTMS (4.85 g, 37.82 mmol) was added at room temperature. The resulting solution was stirred overnight before water (100 mL) and Et 2 O (100 mL) were added and the phases were separated. The aqueous phase was acidified using solid NaHSO 4 until pH 1 was reached. The aqueous phase was then extracted using EtOAc. The combined organic extract was dried (MgSO 4 ), filtered, and concentrated. Step C
  • Step B The product of Step B (18.91 mmol) was dissolved in dry CH 2 Cl 2 (60 mL) and DIPEA (10 mL, 56.7 mmol), HOBt (5.1 g, 37.82 mmol), and EDCI (5.4 g, 28.36 mmol) were added to the solution. The resulting mixture was stirred for 1 h before NH 3 (30 mL, 2 M in iPrOH, 56.7 mmol) was added. After 1 h of stirring at 25 0 C, the solution was diluted with CH 2 Cl 2 (200 mL) and washed with NaHSO 4 solution, 1 M NaOH, water, dried (Na 2 SO 4 ) and filtered. The residue was purified over silica gel using 5% MeOH in CH 2 Cl 2 to provide the title compound as a solid.
  • HATU (0.64 g, 1.67 mmol) was added in one portion to a stirred solution of 2-(4- chloro-phenoxy)-2-methyl-propionic acid (0.3 g, 1.50 mmol) and the product of Step B of Example 37B (0.27 g, 1.53 mmol), and DIPEA (0.73 mL, 4!2 mmol) in dry DMF (7 mL).
  • the reaction was allowed to stir for 5 hours before it was diluted with CH 2 Cl 2 and washed with NaHSO 4 solution, IM NaOH, brine, and dried (Na 2 SO 4 ), and evaporated. The residue was purified over silica gel using 20% EtOAc / hexanes and concentrated to yield a white solid.
  • Step B To the product of Step A (87 mg, 0.209 mmol) was added NH 3 OHCl (87 mg, 1.25 mmol), DIPEA (0.29 mL, 1.67 mmol) and dry DMSO (1 mL). The resulting solution was heated at 80 0 C for 8 hrs. The solvent was evaporated and the residue was purified on HPLC using CH 3 CN / water 1% TFA as eluent to provide the title compound as an oil.
  • reaction mixture was stirred at room temperature for 72 hours, concentrated in vacuo, and the residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of
  • Example 4OA was prepared according to the procedure outlined in Example 25A, substituting 4-chloro-benzenethiol for 2,3-dimethylphenol.
  • Example 25B The title compound was prepared according to the procedure outlined in Example 25B, substituting the product of Example 4OA for the product of Example 25A.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ ppm 7.42-7.45 (m, 2H), 7.36-7.39 (m, 2H), 7.11-7.21 (m, IH), 3.72- 3.78 (m, IH), 1.91-1.94 (m, 2H), 1.79-1.92 (m, 6H), 1.75-1.80 (m, 3H), 1.44 (s, 8H).
  • the filtrate was concentrated under reduced pressure to provide crude product that was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of 40mL/min. to afford the title compound.
  • Example 44C 2- [4-Chloro-2-(p yrrolidine- 1 -sulfonylVphenoxy] -2-methyl-propionic acid
  • the product of Example 44B (1.0 g, 3.82 mmol) and l,l,l-trichloro-2-methyl-2- propanol hydrate (1.832 g, 10.32 mmol) were dissolved in acetone (8.5 mL). Powdered NaOH (0.47 g. 11.75 mmol) was added with cooling. The resulting mixture was stirred for 1.5 hr at 25°C. A second batch of powdered NaOH (0.47 g) was added and stirred for another 1.5 hrs.
  • Example 7B The product of Example 7B (75 mg, 0.305 mmol), the product of Example 44C (116 mg, 0.335 mmol), and TBTU (108 mg, 0.336 mmol) were suspended in dimethylacetamide (0.5 mL). Diisopropylethylamine (135 mg, 1.05 mmol) was added and the resulting solution stirred at 25°C for 15 hrs. Toluene was added, and concentrated. More toluene was added, and washed with dil H 3 PO 4 , H 2 O, and then KHCO 3 . The organic phase was dried (Na 2 SO 4 ), and filtered. The solvents were removed in vacuo and the residue crystallized from ether and heptane to yield the title compound (133 mg), m.p. 152-154 0 C.
  • Example 44E The product of Example 44E (76 mg, 0.145 mmol), TBTU (52 mg, 0.162 mmol), and diisopropylethylamine (40 mg, 0.31 mmol) were dissolved in N 5 N-dimethylacetamide (0.3 niL). After 25 min. at 25°C, a solution of 10% ammonia in THF was added. A solid formed and the mixture was stirred for3 hrs at 25°C. Toluene was added and the mixture concentrated in vacuo. The residue was dissolved in CHCl 3 and washed with dil H 3 PO 4 , H 2 O, and KHCO 3 ; dried (Na 2 SO 4 ), filtered and concentrated in vacuo.
  • Example 45A was prepared according to the procedure outlined in Example 44C, substituting 4-(methanesulfonyl)-phenol for the product of Example 44B.
  • Example 45B was prepared according to the procedure outlined in Example 44D, substituting the product of Example 45A for the product of Example 44C.
  • Example 45 C Example 45C was prepared according to the procedure outlined in Example 44E, substituting the product of Example 45B for the product of Example 44D.
  • Example 45D E-4-((2-Methyl-2-[4-(methylsulfonyl)phenoxyl ⁇ 3ropanoyl>amino)adamantane-l-carboxamide
  • Example 44F The title compound was prepared according to the procedure outlined in Example 44F, substituting the product of Example 45C for the product of Example 44E.
  • the product had m.p. 217-219 0 C.
  • MS (ESI+) m/z 435 (M+H) + .
  • Example 46D was prepared according to the procedure outlined in Example 44D substituting the product of Example 46C for the product of Example 44C.
  • Example 46E was prepared according to the procedures outlined in Example 44E substituting the product of Example 46D for the product of Example 44D.
  • Example 44F The title compound was prepared according to the procedure outlined in Example 44F, substituting the product of Example 46E for the product of Example 44E.
  • Example 47A was prepared according to the procedure outlined in Example 44B, substituting diethylamine for pyrrolidine.
  • Example 47B was prepared according to the procedure outlined in Example 44C, substituting the product of Example 47A for the product of Example 44B.
  • Example 47C was prepared according to the procedure outlined in Example 44D, substituting the product of Example 47B for the product of Example 44C.
  • Example 47D was prepared according to the procedure outlined in Example 44E, substituting the product of Example 47C for the product of Example 44D.
  • Example 44F The title compound was prepared according to the procedure outlined in Example 44F, substituting the product of Example 47D for the product of Example 44E.
  • the compound had m.p. 159-161°C.
  • Example 48 A The product of Example 48 A (3.21 g, 13.3 mmol) was dissolved in CH 2 Cl 2 (30 mL), cooled to -78°C and treated with BBr 3 (8.31 g, 3.26 mmol). The resulting dark red solution was stirred at 25°C for 4 min, then cooled to -78°C. Methanol (100 mL) was added slowly. The solution was concentrated in vacuo. Toluene was added to the crude and concentrated again. After adding more toluene, the solution was washed with water and concentrated in vacuo. The residue was dissolved in ether and extracted with NaOH (1.0 g) in water (8 mL). The aqueous layer was removed and stirred 15 minutes, then acidified with concentrated HCl.
  • Example 48C was prepared according to the procedure outlined in Example 44C, substituting the product of Example 48B for the product of Example 44B.
  • Example 48D Example 48D was prepared according to the procedure outlined in Example 44D, substituting the product of Example 48C for the product of Example 44C.
  • Example 48E was prepared according to the procedure outlined in Example 44E, substituting the product of Example 48D for the product of Example 44D.
  • Example 44F The title compound was prepared according to the procedure outlined in Example 44F, substituting the product of Example 48E for the product of Example 44E.
  • the compound had m.p. 206-209°C.
  • Example IA The product of Example IA (175 mg, 1.05 mmol), 2-(4-fluoro-2-chlorophenoxy)-2- methyl-propionic acid (232 mg, 1.00 mmol), and TBTU (353 mg, 1.1 mmol) were dissolved in N,N-dimethylacetamide. Di-isopropylethylamine (258 mg, 2.0 mmol) was added and the mixture was stirred forl ⁇ hrs at 25°C. After that the reaction mixture was concentrated in vacuo. The residue was dissolved in toluene and washed with aqueous H 3 PO 4 solution, and then aqueous KHCO 3 solution. The organic phase was dried with Na 2 SO 4 , and filtered.
  • Example 50A was prepared according to the procedure outlined in Example 44D, substituting the product of Example 49A for the product of Example 44C.
  • Example 5OB Example 50B was prepared according to the procedure outlined in Example 44E, substituting the product of Example 50A for the product of Example 44D.
  • Step B The solution of the product of Step A (207 mg, 0.506 mmol) in dioxane (0.5 mL) and pyridine (100 mg) was treated with trifluoroacetic anhydride (167 mg, 0.795 mmol). The mixture was stirred 5 hr at 25 0 C and concentrated in vacuo after adding toluene.
  • Example 51 2-(2-Chloro-4-fluorophenoxyV2-methyl-N-[ ' ( ' E)-5-fmethylthioV2-adamantyl1propanamide
  • CF 3 COOH 750 mg
  • trifluoroacetic anhydride 375 mg, 1.78 mmol
  • CF 3 COOH (1.68 g, 14.9 mmol
  • NaSCH 3 549 mg, 7.8 mmols
  • Example 51 A-solution of the product of Example 51 (71 mg, 0.172 mmol) in acetic acid (75 mL) was prepared. Sodium perborate (NaBO 3 -H 2 0, 18 mg, 0.18 mmol) was added and the mixture was stirred 16 hr at 25°C. Toluene was added. The mixture was concentrated and more toluene added. This was washed with K 2 CO 3 , dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. The residue was crystallized from ether to get the title compound (44 mg, m.p. 134-135°C).
  • Example 54A The product of Example 54A (4.19 g, 18.3 mmol), ethylene glycol (2.05 mL, 36.6 mmol), and a catalytic amount of p-toluenesulfonic acid (20 mg) were dissolved in benzene (100 mL) and heated at reflux with a Dean-Stark apparatus attached for 16 hours (M. Xie, W. J. Ie Noble, J. Org. Chem. 54: 3836-3839, 1989). The reaction was cooled, washed with 2N sodium carbonate, water, and brine. The organic solution was dried (Na 2 SO 4 ), filtered, and evaporated under reduced pressure to provide the title compound.
  • Example 54D (2R. 4R, 5SV3-(4-ToluenesulfonylV3.3a.8.8a-tetrahvdro-l-oxa-2-thia-3-aza- cyclopenta[a]indene-2-oxide and (2S. 4R. 5SV3-r4-ToluenesulfonylV3.3a.8.8a-tetrahvdro-l-oxa-2-thia-3-aza- cyclopenta
  • Reaction was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, IN phosphoric acid, and brine. Organic phase dried (Na 2 SO 4 ), filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (20-30% ethyl acetate in hexane) to provide the title compound.
  • Example 55 A Ethyl l-(4-chlorophenoxy)cyclobutanecarboxylic acid
  • a mixture of p-chlorophenol (621 mg, 4.83 mmol), ethyl 1- bromocyclobutanecarboxylate (1.0 g, 4.83 mmol) and potassium carbonate (1.33 g, 9.66 mmol) in DMF (14.5 ml) was stirred and heated to about 55-60 °C under a nitrogen atmosphere for about 18 hours.
  • the solvent was removed under high vacuum, the residue was taken up in diethyl ether (50 ml) and was washed with water and brine (15 ml each).
  • the organic layer was dried (MgSO 4 ), and filtered.
  • Example 55C E-4-( ⁇ ri-(4-Chlorophenoxy)cvclobutyl1carbonyl>amino)adamantane-l- carbo ⁇ ylic acid methyl ester
  • Example 55B A mixture of the product of Example 55B (207 mg, 0.81 mmol), the product of Example 7B (200 mg, 0.81 mmol), O-benzotriazol-l-yl- ⁇ N ⁇ N'-tetramethyluronium tetrafluoroborate (523 mg, 1.63 mmol) and iV,N-diisopropylethylamine (0.57 ml, 3.26 mmol) in DMF (11 ml) was stirred at ambient temperature under a nitrogen atmosphere for about 18 hours.
  • Step A The product of Step A was dissolved in a mixture of THF, water, and ethanol and treated with excess NaOH. After stirring at room temperature overnight the reaction was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC using acetonitrile:10mM NH 4 OAc on YMC Guardpak column to provide the title compound (25 mg, 10%).
  • Example 33B The product of Example 33B (0.1 g, 0.266 mmol) and glyoxal (0.11 g, 40 wt% in water, 0.8 mmol) was dissolved in ammonia solution (6 mL, 7 N). The reaction vessel was sealed and stirred at room temperature for 1 day. The volatiles were evaporated and the residue was purified by reverse phase HPLC using CH 3 CN / 0.1% TFA in. water to provide the title compound as an oil.
  • Dess-Matin periodinane (1 g, 2.43 mmol) was added in one portion to a solution of the product of Step A (0.65 g, 1.62 mmol) in dry CH 2 Cl 2 .
  • the resulting solution was stirred for 3 hours at room temperature before it was quenched with saturated NaHCO 3 solution and Na 2 S 2 O 3 solution.
  • the mixture was stirred for 1 hour before the phases were separated.
  • the organic phase was dried (Na 2 SO 4 ), filtered, and the solvent was evaporated. The residue was purified over silica gel using 30% EtOAc in haxanes to provide the title compound as a yellow solid.
  • Example 44C The title compound was prepared according to the procedure outlined in Example 44C substituting 2-chlorophenol for the product of Example 44B.
  • Example 54J The title compound was prepared according to the procedure outlined in Example 54J substituting the product of Example 62A for 2-(4-chlorophenoxy)-2-methylpropionic acid.
  • Example 44C The title compound was prepared according to the procedure outlined in Example 44C, substituting 2-methylphenol for the product of Example 44B.
  • Example 54J The title compound was prepared according to the procedure outlined in Example 54J substituting the product of Example 63 A for 2-(4-chlorophenoxy)-2-methyl ⁇ ropionic acid.
  • Example 44C The title compound was prepared according to the procedure outlined in Example 44C, substituting 4-methylphenol for the product of Example 44B.
  • Example 54J The title compound was prepared according to the procedure outlined in Example 54J substituting the product of Example 64A for 2-(4-chlorophenoxy)-2-methylpropionic acid.
  • MS (ESI+) m/z 407 (M+H) + .
  • Example 44C The title compound was prepared according to the procedure outlined in Example 44C, substituting 2-trifluoromethylphenol for the product of Example 44B.
  • Example 65B N-[rE)-5-(AminosulfonylV2-adamantyll-2-methyl-2-r2- ftrifluoromethvDphenoxyjpropanamide The title compound was prepared according to the procedure outlined in Example 54J substituting the product of Example 65 A for 2-(4-chlorophenoxy)-2-methyl ⁇ ropionic acid.
  • Example 54J The title compound was prepared according to the procedure outlined in Example 54J substituting the product of Example 66 A for 2-(4-chlorophenoxy)-2-methylpropionic acid.
  • MS (ESI+) m/z 427 (M+H) + .
  • Example 67 N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-(2-chloro-4-fluorophenoxy)-2- methylpropanamide
  • the title compound was prepared according to the procedure outlined in Example 54J substituting the product of Example 49 A for 2-(4-chlorophenoxy)-2-methylpropionic acid.
  • Biological Data Measurement of Inhibition Constants: The ability of test compounds to inhibit human ll ⁇ -HSD-1 enzymatic activity in vitro was evaluated in a Scintillation Proximity Assay (SPA). Tritiated-cortisone substrate, NADPH co factor and titrated compound were incubated with truncated human 1 l ⁇ -HSD-1 enzyme (24-287 AA) at room temperature to allow the conversion to Cortisol to occur. The reaction was stopped by adding a non-specific 11 ⁇ -HSD inhibitor, 1 B ⁇ -glycyrrhetinic acid.
  • SPA Scintillation Proximity Assay
  • the tritiated Cortisol was captured by a mixture of an anti-cortisol monoclonal antibody and SPA beads coated with anti-mouse antibodies.
  • the reaction plate was shaken at room temperature and the radioactivity bound to SPA beads was then measured on a ⁇ -scintillation counter.
  • the 11- ⁇ HSD-l assay was carried out in 96-well microtiter plates in a total volume of 220 ⁇ l. To start the assay, 188 ⁇ l of master mix which contained 17.5 nM H-cortisone, 157.5 nM cortisone and 181 mM NADPH was added to the wells. In order to drive the reaction in the forward direction, 1 mM G-6-P was also added.
  • E.coli lysates overexpressing 11 ⁇ -HSD- 1 enzyme After shaking and incubating plates for 30 minutes at room temperature, reactions were stopped by adding 10 ⁇ l of 1 mM glycyrrhetinic acid. The product, tritiated Cortisol, was captured by adding 10 ⁇ l of 1 ⁇ M monoclonal anti- cortisol antibodies and 100 ⁇ l SPA beads coated with anti-mouse antibodies. After shaking for 30 minutes, plates were read on a liquid scintillation counter Topcount. Percent inhibition was calculated based on the background and the maximal signal. Wells that contained substrate without compound or enzyme were used as the background, while the wells that contained substrate and enzyme without any compound were considered as maximal signal.
  • Percent of inhibition of each compound was calculated relative to the maximal signal and IC 50 curves were generated. This assay was applied to 1 l ⁇ -HSD-2 as well, whereby tritiated Cortisol and NAD + were used as substrate and cofactor, respectively.
  • Compounds of the present invention are active in the 11- ⁇ HSD-l assay described above and show selectivity for human 11- ⁇ -HSD-l over human 1 l- ⁇ -HSD-2, as indicated in Table 1.
  • Table 1 11- ⁇ -HSD-l and 1 l- ⁇ -HSD-2 activity for representative compounds.
  • the data in Table 1 demonstrates that compounds A, B, C, D and E are active in the human ll ⁇ -HSD-1 enzymatic SPA assay described above and that the tested compound showed selectivity for ll ⁇ -HSD-1 over ll ⁇ -HSD-2.
  • the ll ⁇ -HSD-1 inhibitors of this invention generally have an inhibition constant IC 50 of less than 600 nM and preferably less than 50 nM.
  • the compounds preferably are selective, having an inhibition constant IC 50 against 1 l ⁇ -HSD-2 greater than 1000 nM and preferably greater than 10,000 nM.
  • the IC 50 ratio for ll ⁇ -HSD-2 to ll ⁇ -HSD-1 of a compound is at least 10 or greater and preferably 100 or greater.
  • Metabolic stability screen each substrate (10 ⁇ M) was incubated with microsomal protein (0.1 - 0.5 mg/ml) in 5OmM potassium phosphate buffer (pH 7.4) in 48-Well plate. The enzyme reaction was initiated by the addition of ImM NADPH, then incubated at 37 0 C in a Forma Scientific incubator (Marietta, OH, USA) with gentle shaking. The reactions were quenched by the addition of 800 ⁇ l of ACN/MeOH (1:1, v/v), containing 0.5 ⁇ M of internal standard (IS), after 30 min incubation.
  • ACN/MeOH 1:1, v/v
  • IS internal standard
  • the parent remaining in the incubation mixture was determined by LC/MS.
  • the LC/MS system consisted of an Agilent 1100 series (Agilent Technologies, Waldbronn, Germany) and API 2000 (MDS SCIEX, Ontario, Canada).
  • a Luna C8(2) 50 x 2.0 mm, particle size 3 ⁇ m, Phenomenex, Torrance, CA, USA was used to quantify each compound at ambient temperature.
  • the mobile phase consisted of (A): 10 mM NH 4 AC (pH 3.3) and (B): 100% ACN and was delivered at a flow rate of 0.2 ml/min. Elution was achieved using a linear gradient of 0-100% B over 3 min, then held 100% B for 4 min and returned to 100% A in 1 min. The column was equilibrated for 7 min before the next injection.
  • the peak area ratios (each substrate over IS) at each incubation time were expressed as the percentage of the ratios (each substrate over IS) of the control samples (0 min incubation).
  • the parent remaining in the incubation mixture was expressed as the percentage of the values at 0 min incubation.
  • Glucocorticoids are steroid hormones that play an important role in regulating multiple physiological processes in a wide range of tissues and organs.
  • glucocorticoids are potent regulators of glucose and lipid metabolism. Excess glucocorticoid action may lead to insulin resistance, type 2 diabetes, dyslipidemia, visceral obesity and hypertension.
  • Cortisol is the major active and cortisone is the major inactive form of glucocorticoids in humans, while corticosterone and dehydrocorticosterone are the major active and inactive forms in rodents.
  • tissue glucocorticoid levels may also be controlled by 11 ⁇ -hydroxysteroid dehydrogenases enzymes (11 ⁇ -HSDs).
  • 11 ⁇ -HSDs 11 ⁇ -hydroxysteroid dehydrogenases enzymes
  • the 1 l ⁇ - hydroxysteroid dehydrogenases type 1 enzyme (1 l ⁇ -HSD-1) is a low affinity enzyme with K m for cortisone in the micromolar range that prefers NADPH/NADP + (nicotinamide adenine dinucleotide) as cofactors.
  • 1 l ⁇ -HSD-1 is widely expressed and particularly high expression levels are found in liver, brain, lung, adipose tissue and vascular smooth muscle cells.
  • In vitro studies indicate that 1 l ⁇ -HSD-I is capable of acting both as a reductase and a dehydrogenase. However, many studies have shown that it is predominantly a reductase in vivo and in intact cells.
  • the 11 ⁇ -hydroxysteroid dehydrogenases type 2 enzyme (11 ⁇ -HSD-2) is a NAD + -dependent, high affinity dehydrogenase with a K m for Cortisol in the nanomolar range.
  • 11 ⁇ -HSD-2 is found primarily in mineralocorticoid target tissues, such as kidney, colon and placenta.
  • Glucocorticoid action is mediated by the binding of glucocorticoids to receptors, such as mineralocorticoid receptors and glucocorticoid receptors. Through binding to its receptor, the main mineralocorticoid aldosterone controls the water and salts balance in the body.
  • 1 l ⁇ -HSD-2 converts Cortisol to inactive cortisone, therefore preventing the non-selective mineralocorticoid receptors from being exposed to high levels of Cortisol.
  • Mutations in the gene encoding 1 l ⁇ -HSD-2 cause Apparent Mineralocorticoid Excess Syndrome (AME), which is a congenital syndrome resulting in hypokaleamia and severe hypertension.
  • AME Patients have elevated Cortisol levels in mineralocorticoid target tissues due to reduced 11 ⁇ -HSD-2 activity.
  • the AME symptoms may also be induced by administration of 1 l ⁇ -HSD-2 inhibitor, glycyrrhetinic acid.
  • 1 l ⁇ -HSD-2 inhibitor glycyrrhetinic acid.
  • the activity of 11 ⁇ -HSD-2 in placenta is probably important for protecting the fetus from excess exposure to maternal glucocorticoids, which may result in hypertension, glucose intolerance and growth retardation. Due to the potential side effects resulting from 1 l ⁇ - HSD-2 inhibition, the present invention describes selective 11 ⁇ -HSD- 1 inhibitors.
  • Glucocorticoid levels and/or activity may contribute to numerous disorders, including Type II diabetes, obesity, dyslipidemia, insulin resistance and hypertension.
  • Administration of the compounds of the present invention decreases the level of Cortisol and other ll ⁇ - hydroxysteroids in target tissues, thereby reducing the effects of glucucocrticoid activity in key target tissues.
  • the present invention could be used for the treatment, control, amelioration, prevention, delaying the onset of or reducing the risk of developing the diseases and conditions that are described herein.
  • glucocorticoids are potent regulators of glucose and lipid metabolism, glucocorticoid action may contribute or lead to insulin resistance, type 2 diabetes, dyslipidemia, visceral obesity and hypertension.
  • Cortisol antagonizes the insulin effect in liver resulting in reduced insulin sensitivity and increased gluconeogenesis. Therefore, patients who already have impaired glucose tolerance have a greater probability of developing type 2 diabetes in the presence of abnormally high levels of Cortisol.
  • Previous studies (B. R. Walker et al., J. of Clin. Endocrinology and Met., 80: 3155-3159, 1995) have demonstrated that administration of non-selective ll ⁇ -HSD-1 inhibitor, carbenoxolone, improves insulin sensitivity in humans. Therefore, administration of a therapeutically effective amount of an ll ⁇ -HSD-1 inhibitor may treat, control, ameliorate, delay, or prevent the onset of type 2 diabetes.
  • glucocorticoids in vivo has been shown to reduce insulin secretion in rats (B. Billaudel et al., Horm. Metab. Res. 11 : 555-560, 1979). It has also been reported that conversion of dehydrocorticosterone to corticosterone by 11 ⁇ -HSD-1 inhibits insulin secretion from isolated murine pancreatic ⁇ cells. (B. Davani et al., J. Biol. Chem., 275: 34841-34844, 2000), and that incubation of isolated islets with an ll ⁇ -HSD-1 inhibitor improves glucose-stimulated insulin secretion (H Orstater et al., Diabetes Metab. Res. Rev.. 21 : 359-366, 2005). Therefore, administration of a therapeutically effective amount of an 11 ⁇ -HSD-1 inhibitor may treat, control, ameliorate, delay, or prevent the onset of type 2 diabetes by improving glucose-stimulated insulin secretion in the pancreas.
  • Abdominal obesity is closely associated with glucose intolerance (C. T. Montaque et al., Diabetes, 49: 883-888, 2000), hyperinsulinemia, hypertriglyceridemia and other factors of metabolic syndrome (also known as syndrome X), such as high blood pressure, elevated VLDL and reduced HDL.
  • metabolic syndrome X also known as syndrome X
  • Animal data supporting the role of 11 ⁇ -HSD-1 in the pathogenesis of the metabolic syndrome is extensive (Masuzaki, et ah. Science. 294: 2166-2170, 2001; Paterson, J.M., et al; Proc Natl. Acad. Sd. USA. 101: 7088-93, 2004; Montague and O'Rahilly. Diabetes. 49: 883-888, 2000).
  • administering may treat, control, ameliorate, delay, or prevent the onset of obesity.
  • Long-term treatment with an 11 ⁇ -HSD-1 inhibitor may also be useful in delaying the onset of obesity, or perhaps preventing it entirely if the patients use an 1 l ⁇ - HSD-I inhibitor in combination with controlled diet, exercise, or in combination or sequence with other pharmacological approaches.
  • reducing insulin resistance and/or maintaining serum glucose at normal concentrations and/or reducing obestity compounds of the present invention also have utility in the treatment and prevention of conditions that accompany Type 2 diabetes and insulin resistance, including the metabolic syndrome or syndrome X, obesity, reactive hypoglycemia, and diabetic dyslipidemia.
  • 1 l ⁇ -HSD-1 is present in multiple tissues, including vascular smooth muscle, where local glucocorticoid levels that are thought to increase insulin resistance, leading to reductions in nitric oxide production, and potentiation of the vasoconstrictive effects of both catecholamines and angiotensin II (M. Pirpiris et al., Hypertension, 19:567-574, 1992, C. Kornel et al., Steroids, 58: 580-587, 1993, B. R. Walker and B. C. Williams, Clin. Sci. 82:597-605, 1992; Hodge, G. et al Exp. Physiol 87: 1-8, 2002).
  • mice overexpressing 1 l ⁇ -HSD-1 in liver and fat are also hypertensive, a phenotype believed to result from glucocorticoid activation of the renin angiotensin system (Paterson, J.M. et al, PNAS. 101: 7088-93, 2004; Masuzaki, H. et al, J. Clin. Invest. 112: 83-90, 2003). Therefore, administration of a therapeutically effective dose of an 11 ⁇ -HSD-I inhibitor may treat, control, ameliorate, delay, or prevent the onset of hypertension.
  • Cushing's syndrome is a life-threatening metabolic disorder characterized by sustained and elevated glucocorticoid levels caused by the endogenous and excessive production of Cortisol from the adrenal glands.
  • Typical Cushingoid characteristics include central obesity, diabetes and/or insulin resistance, moon face, buffalo hump, skin thinning, dyslipidemia, osteoporosis, reduced cognitive capacity, dementia, hypertension, sleep deprivation, and atherosclerosis among others (Principles and Practice of Endocrinology and Metabolism. Edited by Kenneth Becker, Lippincott Williams and Wilkins Pulishers, Philadelphia, 2001; pg 723-8).
  • exogenous glucocorticoids such as prednisone or dexamethasone
  • Endogenous Cushings typically evolves from pituitary hyperplasia, some other ectopic source of ACTH, or from an adrenal carcinoma or nodular hyperplasia.
  • Administration of a therapeutically effective dose of an ll ⁇ -HSD-1 inhibitor may reduce local glucocorticoid concentrations and therefore treat, control, ameliorate, delay, or prevent the onset of Cushing's disease and/or similar symptoms arising from glucocorticoid treatment.
  • glucocorticoids include glucocorticoid-induced acute psychosis which is of major concern to physicians when treating patients with these steroidal agents (Wolkowitz et ah; Ann NY Acad Sd. 1032: 191- 4, 2004).
  • Conditional mutagenesis studies of the glucocorticoid receptor in mice have also provided genetic evidence that reduced glucocorticoid signaling in the brain results in decreased anxiety (Tranche, F. et al. (1999) Nature Genetics 23: 99-103). Therefore, it is expected that potent, selective ll ⁇ -HSD-1 inhibitors would treat, control, ameliorate, delay, or prevent the onset of cognitive decline, dementia, steroid-induced acute psychosis, depression, and/or anxiety.
  • mice 1 l ⁇ -HSD-1 knockout mice are resistant to the dyslipidemic effects of a high fat diet and have an improved lipid profile vs wild type controls (Morton N.M. et al, JBC, 276: 41293-41300, 2001), and mice which overexpress ll ⁇ -HSD-1 in fat exhibit the dyslipidemic phenotype characteristic of metabolic syndrome, including elevated circulating free fatty acids, and triclylgerides (Masuzaki, H., et al Science. 294: 2166-2170, 2001).
  • a selective ll ⁇ - HSD-I inhibitor has also been shown to reduce elevated plasma triglycerides and free fatty acids in mice on a high fat diet, and significantly reduce aortic content of cholesterol esters, and reduce progression of atherosclerotic plaques in mice (Hermanowski-Vosatka, A. et al. J. Exp. Med. 202: 517-27, 2005).
  • the administration of a therapeutically effective amount of an 11 ⁇ -HSD-1 inhibitor would therefore be expected to treat, control, ameliorate, delay, or prevent the onset of dyslipidemia and/or atherosclerosis.
  • Glucocorticoids are known to cause a variety of skin related side effects including skin thinning, and impairment of wound healing (Anstead, G. Adv Wound Care. 11 : 277- 85, 1998; Beer, et a!.; Vitam Harm. 59: 217-39, 2000).
  • ll ⁇ -HSD-1 is expressed in human skin fibroblasts, and it has been shown that the topical treatment with the non-selective HSD1/2 inhibitor glycerrhetinic acid increases the potency of topically applied hydrocortisone in a skin vasoconstrictor assay (Hammami, MM, and Siiteri, PK. J. Clin. Endocrinol. Metab. 73: 326-34, 1991).
  • Cortisol is an important and well-recognized anti-inflammatory agent (J. Baxer, Pharmac. Ther., 2:605-659, 1976), if present in large amount it also has detrimental effects.
  • high glucocorticoid activity shifts the immune response to a humoral response, when in fact a cell based response may be more beneficial to patients.
  • Inhibition of 11 ⁇ -HSD-1 activity may reduce glucocorticoid levels, thereby shifting the immuno response to a cell based response.
  • 11 ⁇ -HSD-1 specific inhibitors could treat, control, ameliorate, delay, or prevent the onset of tuberculosis, psoriasis, stress, and diseases or conditions where high glucocorticoid activity shifts the immune response to a humoral response.
  • NPE nonpigmented epithelial cells
  • Glucocorticoids are known to increase bone resorption and reduce bone formation in mammals (Turner et al. Calcif Tissue Int. 54: 311-5, 1995; Lane, NE et al.
  • Glucocorticoids such as prednisone and dexamethasone
  • Glucocorticoids are also commonly used to treat a variety of inflammatory conditions including arthritis, inflammatory bowl disease, and asthma.
  • These steroidal agents have been shown to increase expression of 1 l ⁇ -HSD-1 mRNA and activity in human osteoblasts (Cooper et al; J. Bone Miner Res. 17: 979-986, 2002).
  • 1 l ⁇ -HSD-1 plays a potentially important role in the development of bone-related adverse events as a result of excessive glucocorticoid levels or activity.
  • compositions of the present compounds comprise an effective amount of the same formulated with one or more therapeutically suitable excipients.
  • therapeutically suitable excipient generally refers to pharmaceutically suitable, solid, semi-solid or liquid fillers, diluents, encapsulating material, formulation auxiliary and the like.
  • therapeutically suitable excipients include, but are not limited to, sugars, cellulose and derivatives thereof, oils, glycols, solutions, buffers, colorants, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents and the like.
  • Such therapeutic compositions may be administered parenterally, intracisternally, orally, rectally, intraperitoneally or by other dosage forms known in the art.
  • Liquid dosage forms for oral administration include, but are not limited to, emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may also contain diluents, solubilizing agents, emulsifying agents, inert diluents, wetting agents, emulsifiers, sweeteners, flavorants, perfuming agents and the like.
  • Injectable preparations include, but are not limited to, sterile, injectable, aqueous, oleaginous solutions, suspensions, emulsions and the like. Such preparations may also be formulated to include, but are not limited to, parenterally suitable diluents, dispersing agents, wetting agents, suspending agents and the like. Such injectable preparations may be sterilized by filtration through a bacterial-retaining filter. Such preparations may also be formulated with sterilizing agents that dissolve or disperse in the injectable media or other methods known in the art. The absorption of the compounds of the present invention may be delayed using a liquid suspension of crystalline or amorphous material having poor water solubility.
  • the rate of absorption of the compounds generally depends upon the rate of dissolution and crystallinity. Delayed absorption of a parenterally administered compound may also be accomplished by dissolving or suspending the compound in oil. Injectable depot dosage forms may also be prepared by microencapsulating the same in biodegradable polymers. The rate of drug release may also be controlled by adjusting the ratio of compound to polymer and the nature of the polymer employed. Depot injectable formulations may also prepared by encapsulating the compounds in liposomes or microemulsions compatible with body tissues.
  • Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, gels, pills, powders, granules and the like.
  • the drug compound is generally combined with at least one therapeutically suitable excipient, such as carriers, fillers, extenders, disintegrating agents, solution retarding agents, wetting agents, absorbents, lubricants and the like.
  • Capsules, tablets and pills may also contain buffering agents.
  • Suppositories for rectal administration may be prepared by mixing the compounds with a suitable non-irritating excipient that is solid at ordinary temperature but fluid in the rectum.
  • the present drug compounds may also be microencapsulated with one or more excipients.
  • Tablets, dragees, capsules, pills and granules may also be prepared using coatings and shells, such as enteric and release or rate controlling polymeric and nonpolymeric materials.
  • the compounds may be mixed with one or more inert diluents. Tableting may further include lubricants and other processing aids.
  • capsules may contain opacifying agents that delay release of the compounds in the intestinal tract.
  • Transdermal patches have the added advantage of providing controlled delivery of the present compounds to the body.
  • Such dosage forms are prepared by dissolving or dispensing the compounds in suitable medium.
  • Absorption enhancers may also be used to increase the flux of the compounds across the skin. The rate of absorption may be controlled by employing a rate controlling membrane.
  • the compounds may also be incorporated into a polymer matrix or gel.
  • disorders of the present invention maybe treated, prophylatically treated, or have their onset delayed in a patient by administering to the patient a therapeutically effective amount of compound of the present invention in accordance with a suitable dosing regimen.
  • a therapeutically effective amount of any one of compounds of formulas I thru DC is administered to a patient to treat and/or prophylatically treat disorders modulated by the 11-beta-hydroxy steroid dehydrogenase type 1 enzyme.
  • the specific therapeutically effective dose level for a given patient population may depend upon a variety of factors including, but not limited to, the specific disorder being treated, the severity of the disorder; the activity of the compound, the specific composition or dosage form, age, body weight, general health, sex, diet of the patient, the time of admim ' stration, route of administration, rate of excretion, duration of the treatment, drugs used in combination, coincidental therapy and other factors known in the art.
  • the present invention also includes therapeutically suitable metabolites formed by in vivo biotransformation of any of the compounds of formula I thru IX.
  • therapeutically suitable metabolite generally refers to a pharmaceutically active compound formed by the in vivo biotransform ation of compounds of formula I thru IX.
  • pharmaceutically active metabolites include, but are not limited to, compounds made by adamantane hydroxylation or polyhydroxylation of any of the compounds of formulas I thru IX.
  • the total daily dose (single or multiple) of the drug compounds of the present invention necessary to effectively inhibit the action of 11-beta-hydroxysteroid dehydrogenase type 1 enzyme may range from about 0.01 mg/kg/day to about 50 mg/kg/day of body weight and more preferably about 0.1 mg/kg/day to about 25 mg/kg/day of body weight.
  • Treatment regimens generally include administering from about 10 mg to about 1000 mg of the compounds per day in single or multiple doses.

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Abstract

The present invention relates to compounds which are inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme. The present invention further relates to the use of inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions that are mediated by excessive glucocorticoid action.

Description

Inhibitors of the ll-beta-hydroxysteroid dehydrogenase Type 1 enzyme
Field of invention
The present invention relates to compounds that are inhibitors of the 11-beta- hydroxysteroid dehydrogenase Type 1 enzyme. The present invention further relates to the use of inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme for the treatment of non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions that are mediated by excessive glucocorticoid action.
Background of the Invention
Insulin is a hormone that modulates glucose and lipid metabolism. Impaired action of insulin (i.e., insulin resistance) results in reduced insulin-induced glucose uptake, oxidation and storage, reduced insulin-dependent suppression of fatty acid release from adipose tissue (i.e., lipolysis) and reduced insulin-mediated suppression of hepatic glucose production and secretion. Insulin resistance frequently occurs in diseases that lead to increased and premature morbidity and mortality.
Diabetes mellitus is characterized by an elevation of plasma glucose levels (hyperglycemia) in the fasting state or after administration of glucose during a glucose tolerance test. While this disease may be caused by several underlying factors, it is generally grouped into two categories, Type 1 and Type 2 diabetes. Type 1 diabetes, also referred to as Insulin Dependent Diabetes Mellitus ("IDDM"), is caused by a reduction of production and secretion of insulin. In type 2 diabetes, also referred to as non-insulin dependent diabetes mellitus, or NIDDM, insulin resistance is a significant pathogenic factor in the development of hyperglycemia. Typically, the insulin levels in type 2 diabetes patients are elevated (i.e., hyperinsulinemia), but this compensatory increase is not sufficient to overcome the insulin resistance. Persistent or uncontrolled hyperglycemia in both type 1 and type 2 diabetes mellitus is associated with increased incidence of macrovascular and/or microvascular complications including atherosclerosis, coronary heart disease, peripheral vascular disease, stroke, nephropathy, neuropathy and retinopathy.
Insulin resistance, even in the absence of profound hyperglycemia, is a component of the metabolic syndrome. Recently, diagnostic criteria for metabolic syndrome have been established. To qualify a patient as having metabolic syndrome, three out of the five following criteria must be met: elevated blood pressure above 130/85 rnmHg, fasting blood glucose above 110 mg/dl, abdominal obesity above 40" (men) or 35" (women) waist circumference and blood lipid changes as defined by an increase in triglycerides above 150 mg/dl or decreased HDL cholesterol below 40 mg/dl (men) or 50 mg/dl (women). It is currently estimated that 50 million adults, in the US alone, fulfill these criteria. That population, whether or not they develop overt diabetes mellitus, are at increased risk of developing the macrovascular and microvascular complications of type 2 diabetes listed above.
Available treatments for type 2 diabetes have recognized limitations. Diet and physical exercise can have profound beneficial effects in type 2 diabetes patients, but compliance is poor. Even in patients having good compliance, other forms of therapy may be required to further improve glucose and lipid metabolism.
One therapeutic strategy is to increase insulin levels to overcome insulin resistance. This may be achieved through direct injection of insulin or through stimulation of the endogenous insulin secretion in pancreatic beta cells. Sulfonylureas (e.g., tolbutamide and glipizide) or meglitinide are examples of drugs that stimulate insulin secretion (i.e., insulin secretagogues) thereby increasing circulating insulin concentrations high enough to stimulate insulin-resistant tissue. However, insulin and insulin secretagogues may lead to dangerously low glucose concentrations (i.e., hypoglycemia), hi addition, insulin secretagogues frequently lose therapeutic potency over time.
Two biguanides, metformin and phenformin, may improve insulin sensitivity and glucose metabolism in diabetic patients. However, the mechanism of action is not well understood. Both compounds may lead to lactic acidosis and gastrointestinal side effects (e.g., nausea or diarrhea). Alpha-glucosidase inhibitors (e.g., acarbose) may delay carbohydrate absorption from the gut after meals, which may in turn lower blood glucose levels, particularly in the postprandial period. Like biguanides, these compounds may also cause gastrointestinal side effects.
Glitazones (i.e., 5-benzylthiazolidine-2,4-diones) are a newer class of compounds used in the treatment of type 2 diabetes. These agents may reduce insulin resistance in multiple tissues, thus lowering blood glucose. The risk of hypoglycemia may also be avoided. Glitazones modify the activity of the Peroxisome Proliferator Activated Receptor ("PPAR") gamma subtype. PPAR is currently believed to be the primary therapeutic target for the main mechanism of action for the beneficial effects of these compounds. Other modulators of the PPAR family of proteins are currently in development for the treatment of type 2 diabetes and/or dyslipidemia. Marketed glitazones suffer from side effects including bodyweight gain and peripheral edema.
Additional treatments to normalize blood glucose levels in patients with diabetes mellitus are needed. Other therapeutic strategies are being explored. For example, research is being conducted concerning Glucagon-Like Peptide 1 ("GLP-I") analogues and inhibitors of Dipeptidyl Peptidase IV ("DPP-IV") that increase insulin secretion. Other examples include: Inhibitors of key enzymes involved in the hepatic glucose production and secretion (e.g., fructose- 1,6-bisphosphatase inhibitors) and direct modulation of enzymes involved in insulin signaling (e.g., Protein Tyrosine Phosphatase- IB, or "PTP-IB").
Another method of treating or prophylactically treating diabetes mellitus includes using inhibitors of 11-β-hydroxysteroid dehydrogenase Type 1 (1 lβ-HSDl). Such methods are discussed in J.R. Seckl et al., Endocrinology, 142: 1371-1376, 2001 and references cited therein. Glucocorticoids are steroid hormones that are potent regulators of glucose and lipid metabolism. Excessive glucocorticoid action may lead to insulin resistance, type 2 diabetes, dyslipidemia, increased abdominal obesity and hypertension. Glucocorticoids circulate in the blood in an active form (i.e., Cortisol in humans) and an inactive form (i.e., cortisone in humans). 11 β-HSD 1 , which is highly expressed in liver and adipose tissue, converts cortisone to Cortisol leading to higher local concentration of Cortisol. Inhibition of 1 lβ-HSDl prevents or decreases the tissue specific amplification of glucocorticoid action thus imparting beneficial effects on blood pressure and glucose- and lipid-metabolism.
Thus, inhibiting 1 lβ-HSDl benefits patients suffering from non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions mediated by excessive glucocorticoid action. Summary of the Invention
All patents, patent applications and literature references cited in the specification are herein incorporated by reference in their entirety.
One aspect of the present invention is directed toward a compound of formula (I)
Figure imgf000005_0001
(I), wherein
A1, A2, A3 and A4 are each individually selected from the group consisting of hydrogen, alkenyl, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cyano, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocyclesulfonyl, halogen, haloalkyl, -NR5-[C(R6 R7)]n-C(O)-R8, -O-[C(R9R10)]p-C(O)-Rπ, -OR12, -S-alkyl, -S(O)-alkyl, -N(R13R14), -CO2R15, -C(O)-N(R16R17), -C(R18R19)-OR20,-C(R21R22)-N(R23R24), -C(=N0H)-N(H)2, -C(R181R19^-C(O)N(R23R24), -S(O)2-N(R25R26), and -C(R18aR19a> S(O)2-N(R25R26);
R18a and R19a are each independently selected from the group consisting of hydrogen and alkyl; n is O or 1; p is O or l;
D is a member selected from the group consisting of a -O-, -S-, -S(O)- and -S(O)2-; E is a member selected from the group consisting of alkyl, alkoxyalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, or R4 and E taken together with the atoms to which they are attached form a heterocycle;
R1 is a member selected from the group consisting of hydrogen and alkyl; R2 is a member selected from the group consisting of hydrogen, alkyl and cycloalkyl; R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl, or R3 and R4 taken together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R5 is a member selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
R6 and R7 are each independently selected from the group consisting of hydrogen and. alkyl, or R6 and R7 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R8 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and -N(R27R28);
R9 and R10 are each independently selected from the group consisting of hydrogen and alkyl, or R9 and R10 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R11 is selected from the group consisting of hydroxy and -N(R29R30); R is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl; R13 and R14 are each independently selected from the group consisting of hydrogen, alkyl, alkylsufonyl, aryl, arylalkyl, aryloxyalkyl, arylsulfonyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl and heterocyclesulfonyl; R15 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
R16 and R17 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkylsufonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl, hydroxy, and - alkyl-C(O)N(R201R202), or, R16 and R17 taken together with the atom to which they are attached form a heterocycle;
R201 and R202 are independently selected from the group consisting of hydrogen and alkyl; R18, R19 and R20 are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl;
R21 and R22 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, cycloalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl and heterocyclesulfonyl;
R23 and R24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxy, alkylsulfonyl, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or, R23 and R24 taken together with the atom to which they are attached form a ring selected from the group consisting of heteroaryl and heterocycle;
R and R are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkylsufonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl, and hydroxy, or, R25 and R26 taken together with the atom to which they are attached form a heterocycle; R and R are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkylsufonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl, heterocyclesulfonyl and hydroxy, or, R27 and R28 taken together with the atom to which they are attached form a heterocycle; and R29 and R30 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkylsufonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl, heterocyclesulfonyl, and hydroxy, or, R29 and R30 taken together with the atom to which they are attached form a heterocycle; provided that, if R1 is hydrogen; then at least one of A1, A2, A3 and A4 is not hydrogen.
A further aspect of the present invention encompasses the use of the compounds of formula (T) for the treatment of disorders that are mediated by 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme, such as non-insulin dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome and other diseases and conditions that are mediated by excessive glucocorticoid action, comprising administering a therapeutically effective amount of a compound of formula (T).
According to still another aspect, the present invention is directed to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) in combination with a pharmaceutically suitable carrier.
Detailed description of the Invention
All patents, patent applications and literature references cited in the specification are herein incorporated by reference in their entirety. One aspect of the present invention is directed toward a compound of formula (T), wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; and A1, R3, R4, D and E are as described in the summary of the invention. Another aspect of the present invention is directed toward a compound of formula (T), wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen;
R3 and R4 are hydrogen; and A1, D and E are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (T), wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 are hydrogen;
D is -O-; and A1 and E are as described in the summary of the invention. Another aspect of the present invention is directed toward a compound of formula (I), wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 are hydrogen; D is -O-;
E is as described in the summary of the invention; and
A1 is selected from the group consisting of A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)-N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=NOH)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R183R1^)-S(O)2-N(R25R26), and -
C(R21R22)-N(R23R24) wherein R12, R15, R16, R17, R18, R19, R18a, R19a, R21, R22, R23, R24, R25, and R26 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 are hydrogen;
D is -O-;
A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=N0H)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24) wherein R12, R15, R16, R17, R18, R19, R18a, R19a, R21, R22, R23, R24, R25, and R26 are as described in the summary of the invention; and E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl.
Another aspect of the present invention is directed toward a compound of formula (I), wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen; R3 is hydrogen; R4 is alkyl; and A1, D and E are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (J); wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen; R3 is hydrogen;
R4 is alkyl;
D is -O-; and A1 and E are as described in the summary of the invention. Another aspect of the present invention is directed toward a compound of formula (I), wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; R3 is hydrogen; R4 is alkyl; D is -O-; E is as described in the summary of the invention; and
A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R183R1^)-C(O)N(R23R24), -C(^NOH)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24) wherein R12, R15, R16, R17, R18, R19, R18a, R19a, R21, R22, R23, R24, R25, and R26 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen; R3 is hydrogen;
R4 is alkyl; D iS -O-; A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=N0H)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24) wherein R12, R15, R16, R17, R18, R19, R18a, R19a, R21, R22, R23, R24, R25, and R26 are as described in the summary of the invention; and
E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl.
Another aspect of the present invention is directed toward a compound of formula (I), wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen;
R3 and R4 are alkyl; and A1, D and E are as described in the summary of the invention. Another aspect of the present invention is directed toward a compound of formula (I), wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen; R3 and R4 are alkyl; D is -O-; and A1 and E are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen; R3 and R4 are alkyl;
D is -O-;
E is as described in the summary of the invention; and
A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=N0H)-N(H)2, -S(O)2-N(R25R26), -CO2R15,
-C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24) wherein R12, R15, R16, R17, R18, R19, R18a, R19a, R21, R22, R23, R24, R25, and R26 are as described in the summary of the invention. Another aspect of the present invention is directed toward a compound of formula (I), wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; R3 and R4 are alkyl;
D is -O-;
A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=NOH)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24) wherein R12, R15, R16, R17, R18, R19, R18a, R19a, R21, R22, R23, R24, R25, and R26 are as described in the summary of the invention; and
E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl. Another aspect of the present invention is directed toward a compound of formula (I), wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 taken together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle; and A1, D and E are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen;
R3 and R4 taken together with the atoms to which they are attached form a cycloalkyl ring; and A1, D and E are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 taken together with the atoms to which they are attached form a cycloalkyl ring;
D is -O-; and A1 and E are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 taken together with the atoms to which they are attached form a cycloalkyl ring;
D is -O-; E is as described in the summary of the invention; and
A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18Rl9)-OR20, -C(O)- N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=NOH)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24) wherein R12, R15, R16, R17, R18, R19, R18a, R19a, R21, R22, R23, R24, R25, and R26 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; R3 and R4 taken together with the atoms to which they are attached form a cycloalkyl ring;
D is -O-;
A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R183R19^-C(O)N(R23R24), -C(=N0H)-N(H)2, -S(O)2-N(R25R26), -CO2R15,
-C(R1SaR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24) wherein R12, R15, R16, R17, R1S, R19, R18a, R19a, R21, R22, R23, R24, R25, and R26 are as described in the summary of the invention; and
E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl.
Another aspect of the present invention is directed toward a compound of formula (I), wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 taken together with the atoms to which they are attached form a cyclopropyl ring; D is -O-;
A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=N0H)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24) wherein R12, R15, R16, R17, R18, R19, R18a, R19a, R21, R22, R23, R24, R25, and R26 are as described in the summary of the invention; and
E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl.
Another aspect of the present invention is directed toward a compound of formula (I), wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 taken together with the atoms to which they are attached form a cyclobutyl ring; D is -O-;
A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=N0H)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24) wherein R12, R15, R16, R17, R18, R19, R18a, R19a, R21, R22, R23, R24, R25, and R26 are as described in the summary of the invention; and
E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl.
Another aspect of the present invention is directed toward a compound of formula (I), wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; and R3 and R4 taken together with the atoms to which they are attached form a heterocycle, and A1, D and E are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 taken together with the atoms to which they are attached form a heterocycle;
D is -O-; and A1 and E are as described in the summary of the invention. Another aspect of the present invention is directed toward a compound of formula (T), wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen;
R3 and R4 taken together with the atoms to which they are attached form a heterocycle;
E is as described in the summary of the invention; D is -O-; and
A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=NOH)-N(H)2, -S(O)2-N(R25R2^CO2R15,
-C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24) wherein R12, R15, R16, R17, R18, R19, R18a, R19a, R21, R22, R23, R24, R25, and R26 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 taken together with the atoms to which they are attached form a heterocycle;
D is -O-; A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=N0H)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24) wherein R12, R15, R16, R17, R18, R19, R18a, R19a 5 R21, R22, R23, R24, R25, and R26 are as described in the summary of the invention; and
E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl.
Another aspect of the present invention is directed toward a compound of formula (I), wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; R4 and E taken together with the atoms to which they are attached form a heterocycle; and A1 and D are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (Tj, wherein
A2, A3 and A4 are hydrogen; R1 and R2 are hydrogen;
R4 and E taken together with the atoms to which they are attached form a heterocycle;
D is -O- and A1 is as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R4 and E taken together with the atoms to which they are attached form a heterocycle;
D is -O-; and
A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -CeNOH)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24) wherein R12, R15, R16, R17, R18, R19, R18a, R19a, R21, R22, R23, R24, R25, and R26 are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), wherein A1 is selected from the group consisting of alkylsulfonyl, arylsulfonyl, cycloalkylsulfonyl, heteroarylsulfonyl and heterocyclesulfonyl;
A2, A3 and A4 are hydrogen; D is -O- ; and R1, R2, R3, R4, and E are as described in the summary of the invention. Another aspect of the present invention is directed toward a compound of formula (I), wherein A1 is -S(O)2-N(R25R26) wherein R25 and R26 are as described in the summary of the invention; A2, A3 and A4 are hydrogen;
D is -0-; and R1, R2, R3, R4, and E are as described in the summary of the invention. Another aspect of the present invention is directed toward a compound of formula (T), wherein A1 is -C(O)-N(R16R17) wherein R16 is selected from the group consisting of hydrogen and alkyl and R17 is selected from the group consisting of arylalkyl and heteroarylalkyl; D is -0-;
A2, A3 and A4 are hydrogen; and R1, R2, R3, R4, and E are as described in the summary of the invention.
Another aspect of the present invention is directed toward a compound of formula (I), wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
D is selected from the group consisting of -S-, -S(O)- and -S(O)2; and A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=N0H)-N(H)2, -S(O)2-N(R25R26), -CO2R15,
-C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24) wherein R12, R15, R16, R17, R18, R19, R18a, R19a, R21, R22, R23, R24, R25, and R26 are as described in the summary of the invention; E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl; and R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl and arylalkyl, or R3 and R4 together with the atom to which they are attached form a cycloalkyl ring.
Another aspect of the present invention is directed to a compound selected from the following group E-4-[(2-methyl-2-phenoxypropanoyl)amino]adamantane-l -carboxamide;
E-4-[(2-methyl-2-{[4-(trifluoromethyl)benzyl]oxy}propanoyl)amino]adamantane-l- carboxamide; E-A-( {2-methyl-2-[(2-methylcyclohexyl)oxy]ρropanoyl} amino)adamantane- 1 - carboxylic acid;
E-A-{ {2-methyl-2- [(3 -methylcyclohexyl)oxy]propanoyl} amino)adamantane- 1 - carboxylic acid; E-A- { [2-(cycloheptyloxy)-2-methylpropanoyl] amino} adamantane- 1 -carboxylic acid;
E-A- {[2-(cyclohexylmethoxy)-2-methylpropanoyl]amino} adamantane- 1 -carboxylic acid;
E-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxylic acid; E-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxamide; E-A-{ {2-methyl-2-[(4-methylcyclohexyl)oxy]propanoyl} amino)adamantane- 1 - carboxamide; jE'-4-[(2-phenoxypropanoyl)amino]adamantane-l-carboxamide; E-A- { [2-methyl-2-(2-methylphenoxy)propanoyl] amino } adamantane- 1 -carboxylic acid; E-4-{[2-methyl-2-(4-methylphenoxy)propanoyl]amino}adamantane-l-carboxylic acid;
E-A- { [2-(2-chlorophenoxy)-2-methylpropanoyl] amino} adamantane- 1 -carboxylic acid; E-A- { [2-(2-methoxyphenoxy)-2-methylpropanoyl] amino} adamantane- 1 -carboxamide; E-A- { [2-(4-methoxyphenoxy)-2-methylpropanoyl] amino} adamantane- 1 -carboxamide; E-4-({2-methyl-2-[3-(trifluoromethyl)phenoxy]propanoyl}amino)adamantane-l- carboxamide;
E-4-{[2-(3-methoxyphenoxy)-2-meth.ylpropanoyl]ammo}adamantane-l-carboxamide; E-2-(4-Chloro-phenoxy)-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide; E- { [2-Methyl-2-(4-methylphenoxy)propanoyl] amino} adamantane- 1 -carboxamide; E-A- { [2-(3-Chlorophenoxy)-2-methylpropanoyl] amino} adamantane- 1 -carboxamide;
E-4-({2-Methyl-2-[4-(trifluoromethoxy)phenoxy]propanoyl}amino)adamantane-l- carboxamide;
E-4-{[2-(3-Bromophenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxylic acid; 4-( { [((E)-4- { [2-(4-Chlorophenoxy)-2-methylpropanoyl] amino } - 1 - adamantyl)carbonyl] amino } methyl)benzoic acid;
-Z?-4-{[2-(2,3-Dimethylphenoxy)-2-metliylpropanoyl]amino}adamantane-l-carboxylic acid; tert-Butyl 4-(2- { [(E)-5-(aminocarbonyl)-2-adaniantyl] amino} - 1 , 1 -dimethyl-2- oxoethoxy)phenylcarbamate;
E-N-[4-(Aminocarbonyl)benzyl]-4-{[2-(4-chloroplienoxy)-2- methylpropanoyl] amino } adamantane- 1 -carboxamide;
E-N-[4-(Ammocarbonyl)methyl]-4-{[2-(4-clilorophenoxy)-2- methylpropanoyl] amino } adamantane- 1 -carboxamide;
3-({[((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-l- adamantyl)carbonyl]amino}methyl)benzoic acid; E-4-({2-[(5-Bromopyridin-2-yl)oxy]-2-methylpropanoyl}amino)adamantane-l- carboxamide;
E-A- {[2-(2-Cyanophenoxy)-2-methylpropanoyl] amino } adamantane- 1 -carboxamide;
E-4- { [2-(4-Hydroxyphenoxy)-2-methylpropanoyl] amino} adamantane- 1 -carboxamide;
((E)-4- { [2-(4-Chlorophenoxy)-2-methylpropanoyl] amino} - 1 -adamantyl)acetic acid; N-[(E)-5-(2-Amino-2-oxoethyl)-2-adamantyl]-2-(4-chlorophenoxy)-2- methylpropanamide;
2-(4-Chlorophenoxy)-2-methyl-N-[(E)-5-(2H-tetraazol-5-ylmetliyl)-2- adamantyljpropanamide;
N-{(E)-5-[(Aminosulfonyl)meth.yl]-2-adamantyl}-2-(4-chlorophenoxy)-2- methylpropanamide;
N-{(E)-5-[(Z)-Amino(hydroxyimino)methyl]-2-adamantyl}-2-(4-chlorophenoxy)-2- methylpropanamide;
E-N-[4-(Aminosulfonyl)benzyl]-4-{[2-(4-chlorophenoxy)-2- methylpropanoyl]amino}adamantane-l-carboxamide; E-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-N-(4-
{[(methylsulfonyl)amino]carbonyl}benzyl)adamantane-l-carboxamide;
E-4-({2-[(4-Chlorophenyl)thio]-2-methylpropanoyl}amino)adamantane-l-carboxylic acid;
E-4-({2-[(4-Methoxyphenyl)thio]-2-methylpropanoyl}amino)adamantane-l- carboxamide amide;
E-4-({2-[(4-Methoxyphenyl)sulfinyl]-2-methylpropanoyl}amino)adamantane-l- carboxamide; E-4-({2-[(4-Methoxyphenyl)sulfonyl]-2-methylpropanoyl}ainino)adamantane-l- carboxamide;
E-4-({2-[4-Chloro-2-(pyrrolidin-l-ylsulfonyl)phenoxy]-2- methylpropanoyl}amino)adamantane-l-carboxaniide; E-4-( {2-Methyl-2-[4-(methylsulfonyl)phenoxy]propanoyl} amino)adamantane- 1 - carboxamide;
E-4-({2-Methyl-2-[2-(methylsulfonyl)phenoxy]propanoyl}amino)adamantane-l- carboxamide;
E-4-[(2- {4-Chloro-2-[(diethylamino)sulfonyl]phenoxy} -2- methylpropanoyl)amino] adamantane- 1 -carboxamide;
E-4-({2-Methyl-2-[4-(pyrrolidin-l- ylsulfonyl)phenoxy]propanoyl} amino)adamantane- 1 -carboxamide;
2-(2-Chloro-4-fluorophenoxy)-N-[(£)-5-hydroxy-2-adamantyl]-2- methylpropanamide; 2-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(2H-tetraazol-5-yl)-2- adamantyljpropanamide;
2-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(methylthio)-2- adamantyl]propanamide;
2-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(£)-5-(methylsulfonyl)-2- adamantyl]propanamide;
2-(2-Chloro-4-fluoroρhenoxy)-2-methyl-N-[(E)-5-(methylsulfmyl)-2- adamantyl]propanamide;
N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-(4-chlorophenoxy)-2-methylpropanamide;
E-4-( { [ 1 -(4-Chlorophenoxy)cyclobutyl] carbonyl} amino)adamantane- 1 -carboxamide; 4-[({[((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino}-l- adamantyl)methyl] sulfonyl} amino)methyl]benzoic acid;
2-(4-Chlorophenoxy)-N-[(E)-5-(lH-imidazol-2-yl)-2-adamantyl]-2- methylpropanamide;
(2E)-3-((£)-4-{[2-(4-Chloroρhenoxy)-2-methylρroρanoyl]amino}-l- adamantyl)acrylic acid;
(E)-4-[(2-Methyl-2-{[5-(lH-pyrazol-l-yl)pyridin-2- yl]oxy}propanoyl)amino]adamantane-l-carboxamide; 2-(4-Chlorophenoxy)-N-[(E)-5-isoxazol-5-yl-2-adamantyl]-2-methylpropanamide;
2-(4-Chlorophenoxy)-2-r-iethyl-N-{(E)-5-[(2-morpholin-4-yletlioxy)methyl]-2- adamantyl}propanamide;
N-[(E)-5-(Aniinosulfonyl)-2-adamantyl]-2-(2-chlorophenoxy)-2-methylpropanamide; N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-metliyl-2-(2-metliylphenoxy)propanamide;
N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-(4-methylphenoxy)propanamide;
N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-[2- (trifluoromethyl)phenoxy]propanamide;
N-[(E)-5-(Aniinosulfonyl)-2-adamantyl]-2-metliyl-2-[2- (trifluoromethoxy)phenoxy]propanamide;
N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-(2-chloro-4-fluorophenoxy)-2- methylpropanamide;
E-4-{[2-(2-chlorophenoxy)-2-methyl-3-phenylpropanoyl]amino}adamantane-l- carboxamide; 2-(4-chlorophenoxy)-N-[(£)-5-hydroxy-2-adamantyl]-2-methylpropanamide;
E-4-({2-methyl-2-[(5-morpholin-4-ylpyridin-2-yl)oxy]propanoyl}aniino)adamantane- 1 -carboxamide;
E-4-{[2-methyl-2-(pyridin-2-yloxy)propanoyl]ammo}adamantane-l-carboxamide;
2-(4-chlorophenoxy)-2-methyl-N- { E)-5-[(methylamino)sulfonyl]-2- adamantyl}propanamide;
3 -((E)-4- { [2-(4-chlorophenoxy)-2-methylpropanoyl] amino } - 1 -adamantyl)propanoic acid;
2-(4-chlorophenoxy)-N-{(E)-5-[(dimethylamino)sulfonyl]-2-adamantyl}-2- methylpropanamide; E-4-[(2-{[5-(lH-imidazol-l-yl)pyridin-2-yl]oxy}-2- methylpropanoyl)amino] adamantane- 1 -carboxamide;
2-(4-chlorophenoxy)-2-methyl-N-[(E)-5-(lH-pyrazol-3-yl)-2- adaiiiantyljpropanamide;
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(3-chlorophenoxy)-2-methylpropanamide; N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-methyl-2-(3-methylplienoxy)propanamide;
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(2-metlioxyplienoxy)-2- methylpropanamide; N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(3-metlioxyphenoxy)-2- methylpropanamide;
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-methoxyphenoxy)-2- methylpropanamide; N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-cyanophenoxy)-2-metliylpropanamide;
E-4-{[2-methyl-2-(2-methylphenoxy)propanoyl]amino}adamantane-l-carboxamide;
E-4- {[2-methyl-2-(3-methylphenoxy)propanoyl]amino} adamantane-1 -carboxamide;
E-4-[(2-methyl-2-{[(lS,2S)-2-methylcyclohexyl]oxy}propanoyl)amino]adamantane- 1-carboxylic acid; E-4-({2-methyl-2-[(2-niethylcyclohexyl)oxy]propanoyl}ammo)adamantane-l- carboxamide
E-4- { [2-(cycloheptyloxy)-2-methylpropanoyl] amino } adamantane- 1 -carboxamide;
E-4- { [2-(cyclohexylmethoxy)-2-methylpropanoyl] amino } adamantane- 1 - carboxamide; E-4-({2-methyl-2-[(3-methylcyclohexyl)oxy]propanoyl}amino)adamantane-l- carboxamide;
E-4-{[2-(2-crilorophenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxamide;
4- { [( {(E)-4-[(2-methyl-2-phenoxypropanoyl)amino] - 1 - adamantyl} carbonyl)amino]methyl}benzoic acid; E-4-({2-[(4,4-dimethylcyclohexyl)oxy]-2-methylpropanoyl}amino)adamantane-l- carboxylic acid;
E-4- {[2-methyl-2-(l ,2,3,4-tetrahydronaphthalen-2- yloxy)propanoyl] amino } adamantane- 1 -carboxylic acid;
E-4-{[2-(4-bromoρhenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxylic acid;
E-4- { [2-methyl-2-( 1 -naphthyloxy)propanoyl] amino} adamantane- 1 -carboxylic acid;
E-4- { [2-(2,3-dichlorophenoxy)-2-methylpropanoyl] amino} adamantane- 1 -carboxylic acid;
E-4- {[2-(2,4-dichlorophenoxy)-2-methylpropanoyl] amino} adamantane- 1-carboxylic acid;
E-4-{[2-(2,5-dichlorophenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxylic acid; E-4- {[2-(2,4-dimethylphenoxy)-2-niethylpropanoyl] amino} adamantane- 1 -carboxylic acid;
E-4-{[2-(2,5-dimethylphenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxylic acid; E-4-{[2-methyl-2-(2-naphthyloxy)propanoyl]amino}adamantane-l-carboxylic acid;
£-4-{[2-(4-bromo-2-fluorophenoxy)-2-methylpropanoyl]amino}adamantane-l- carboxylic acid;
£-4-({2-methyl-2-[(7-methyl-2,3-dihydro-lH-inden-4- yl)oxy]propanoyl} amino)adamantane- 1 -carboxylic acid; E-4- { [2-(4-bromo-2-chlorophenoxy)-2-methylpropanoyl] amino} adamantane- 1 - carboxylic acid;
E-4- { [2-( 1 , 1 '-biphenyl-3 -yloxy)-2-methylpropanoyl] amino} adamantane- 1 -carboxylic acid;
E-4-{[2-(2-bromophenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxylic acid;
£'-N-[4-(ammocarbonyl)benzyl]-4-[(2-methyl-2- phenoxypropanoyl)amino] adamantane- 1 -carboxamide;
E-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}-N-(l,3-thiazol-5- ylmethyl)adamantane- 1 -carboxamide; E-4- { [2-(4-chlorophenoxy)-2-methylpropanoyl] amino } -N-(pyridin-4- ylmethyl)adamantane- 1 -carboxamide;
E-4-{[2-(4-aminophenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxamide;
E-4-({2-methyl-2-[2-(trifluoromethoxy)phenoxy]propanoyl}amino)adamantane-l- carboxamide; E-4-( {2-methyl-2-[2-(trifluoromethyl)plienoxy]propanoyl} amino)adamantane- 1 - carboxamide;
E-4-{ {2-methyl-2- [4-(pyrrolidin- 1 - ylsulfonyl)phenoxy]propanoyl} amino)adamantane-l -carboxamide;
2-(2-chloro-4-fluorophenoxy)-N-[(£)-5-hydroxy-2-adamantyl]-2τmethylρropanamide; 2-(2-chloro-4-fluorophenoxy)-N-[(E)-5-cyano-2-adamantyl]-2-methylpropanamide;
E-4-[(2-methyl-2-{4-[(trifluoroacetyl)amino]phenoxy}propanoyl)ammo] adamantane- 1 -carboxamide; E-4- { [2-(3 -bromo-4-methoxyphenoxy)-2-methylpropanoyl] amino } adamantane- 1 - carboxamide;
E-4- {[2-(2,5-dibromo-4-methoxyphenoxy)-2-niethylpropanoyl]amino} adamantane- 1 - carboxamide; £r-4-{[2-(2-bromo-4-methoxyplienoxy)-2-methylpropanoyl]amino}adamantane-l- carboxamide;
E-4-{[2-(2-chloro-4-fluorophenoxy)-2-methylpropanoyl]amino}-N,N- dimethyladamantane- 1 -carboxamide;
2-(4-chlorophenoxy)-N-((E)-5-{[(4-methoxy-6-methylpyrimidin-2-yl)amino]methyl}- 2-adamantyl)-2-methylpropanamide;
E-4-{[2-(4-{[(tert-butylamino)carbonyl]amino}phenoxy)-2- methylpropanoyl] amino } adamantane- 1 -carboxamide; ethyl 4-(2-{[(E)-5-(aminocarbonyl)-2-adamantyl]ammo}-l,l-dimetliyl-2- oxoethoxy)phenylcarbamate; E-4-[(2-methyl-2- {4-[(propylsulfonyl)amino]phenoxy}propanoyl)amino] adamantane-1 -carboxamide;
E-4-[(2-{4-[(3,3-dimethylbutanoyl)amino]phenoxy}-2-methylpropanoyl)amino] adamantane- 1 -carboxamide;
E-4-{[2-methyl-2-(phenylsulfinyl)propanoyl]amino}adamantane-l-carboxylic acid; E-4- {[2-methyl-2-(phenylsulfonyl)propanoyl]amino} adamantane-1 -carboxylic acid;
N-[(E)-5-cyano-2-adamantyl]-2-[(4-methoxyplienyl)sulfonyl]-2-metliylpropanamide;
2-[(4-methoxyphenyl)sulfonyl]-2-methyl-N-[(E)-5-(2H-tetraazol-5-yl)-2- adamantyljpropanamide; and
E-4-({2-[4-(benzyloxy)phenoxy]-2-methylpropanoyl}amino)adamantane-l- carboxamide.
Another embodiment of the present invention discloses a method of inhibiting 11- beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
Another embodiment of the present invention discloses a method of treating disorders in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I). Another embodiment of the present invention discloses a method of treating non- insulin dependent type 2 diabetes in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I). Another embodiment of the present invention discloses a method of treating insulin resistance in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
Another embodiment of the present invention discloses a method of treating obesity in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula
(I)-
Another embodiment of the present invention discloses a method of treating lipid disorders in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
Another embodiment of the present invention discloses a method of treating metabolic syndrome in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type
I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I).
Another embodiment of the present invention discloses a method of treating diseases and conditions that are mediated by excessive glucocorticoid action in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I). Another embodiment of the present invention discloses a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) in combination with a pharmaceutically suitable carrier.
Definition of Terms The term "alkenyl" as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl. Alkenyls of the present invention can be unsύbstituted or substituted with one substituent selected from the group consisting of carboxy, alkoxycarbonyl and aryloxycarbonyl. The term "alkoxy" as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert- butoxy, pentyloxy and hexyloxy.
The term "alkoxyalkyl" as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl and methoxymethyl.
The term "alkoxycarbonyl" as used herein, refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.
The term "alkyl" as used herein, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
The term "alkylcarbonyl" as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl- 1-oxopropyl, 1-oxobutyl and 1-oxopentyl.
The term "alkylsulfonyl" as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of alkylsulfonyl include, but are not limited to, methylsulfonyl and ethylsulfonyl. The term "alkyl-NH" as used herein, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a nitrogen atom.
The term "alkyl-NH-alkyl" as used herein, refers to an alkyl-NH group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
The term "aryl" as used herein, means a phenyl group, or a bicyclic or a tricyclic fused ring system. Bicyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl group, as defined herein, or a heterocycle, as defined herein. Tricyclic fused ring systems are exemplified by an aryl bicyclic fused ring system, as defined herein and fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl group, as defined herein, or a heterocycle, as defined herein. Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl and tetrahydronaphthyl.
The aryl groups of this invention maybe optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl, aryl, arylalkoxy, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl, hydroxy, hydroxyalkyl, nitro, RjR8N-, RfRgNalkyl, RfRgNcarbonyl, -N(H)C(O)N(H)(alkyl), and RfRgNsulfonyl, wherein Rf and Rg are independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, haloalkyl, haloalkylcarbonyl and cycloalkylalkyl wherein the cycloalkyl, the cycloalkyl of cycloalkylalkyl as represented by Rf and Rg are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, alkyl and haloalkyl. The substituent aryl, the aryl of arylalkoxy, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the substituent heteroaryl, the heteroaryl of heteroarylalkyl, the heteroaryl of heteroarylcarbonyl, the substituent heterocycle, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy, the heterocycle of heterocyclesulfonyl may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl wherein Rf and Rg are as described herein.
The term "arylalkyl" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3- phenylpropyl and 2-naphth-2-ylethyl.
The term "arylcarbonyl" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and naphthoyl.
The term "aryl-NH-" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a nitrogen atom. The term "aryl-NH-alkyl" as used herein, refers to an aryl-NH- group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
The term "arylalkoxy" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkoxy moiety, as defined herein.
The term "aryloxy" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
Representative examples of aryloxy include, but are not limited to phenoxy, naphthyloxy, 3- bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy and 3,5-dimethoxyphenoxy.
The term "aryloxyalkyl" as used herein, refers to an aryloxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. The term "aryloxycarbonyl" as used herein, refers to an aryloxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
The term "arylsulfonyl" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of arylsulfonyl include, but are not limited to, phenylsulfonyl, 4- bromophenylsulfonyl and naphthylsulfonyl.
The term "carbonyl" as used herein refers to a -C(O)- group.
The term "carboxy" as used herein refers to a -C(O)-OH group.
The term "carboxyalkyl" as used herein refers to a carboxy group as defined herein, appended to the parent molecular moiety through an alkyl group as defined herein. The term "carboxycycloalkyl" as used herein refers to a carboxy group as defined herein, appended to the parent molecular moiety through an cycloalkyl group as defined herein. The term "cycloalkyl" as used herein, refers to a monocyclic, bicyclic, or tricyclic ring system. Monocyclic ring systems are exemplified by a saturated cyclic hydrocarbon group containing from 3 to 8 carbon atoms. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Bicyclic fused ring systems are exemplified by a cycloalkyl group appended to the parent molecular moiety and fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl group, as defined herein, or a heterocycle, as defined herein. Tricyclic fused ring systems are exemplified by a cycloalkyl bicyclic fused ring system, as defined herein and fused to a cycloalkyl group, as defined herein, a phenyl group, a heteroaryl group, as defined herein, or a heterocycle, as defined herein. Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane. Tricyclic ring systems are also exemplified by a bicyclic ring system in which two non-adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge of between one and three carbon atoms. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.03>7]nonane andtricyclo[3.3.1.13'7]decane (adamantane). The cycloalkyl groups of this invention may be substituted with 1 , 2, 3, 4 or 5 sύbstituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl, wherein Rf and Rg are independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, haloalkyl, haloalkylcarbonyl and cycloalkylalkyl wherein the cycloalkyl, the cycloalkyl of cycloalkylalkyl as represented by Rf and Rg are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, alkyl and haloalkyl. The substituent aryl, the aryl of arylalkyl, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the substituent heteroaryl, the heteroaryl of heteroarylalkyl, the heteroaryl of heteroarylcarbonyl, the substituent heterocycle, the heterocycle of heterocyclealkyl, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy, the heterocycle of heterocyclesulfonyl maybe optionally substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl wherein Rf and Rg are as described herein.
The term "cycloalkylalkyl" as used herein, refers to a cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4- cycloheptylbutyl.
The term "cycloalkylcarbonyl" as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of cycloalkylcarbonyl include, but are not limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl and cyclohexylcarbonyl.
The term "cycloalkyloxy" as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. The term "cycloalkylsulfonyl" as used herein, refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of cycloalkylsulfonyl include, but are not limited to, cyclohexylsulfonyl and cyclobutylsulfonyl.
The term "halo" or "halogen" as used herein, refers to -Cl, -Br, -I or -F. The term "haloalkyl" as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2- fluoroethyl, trifluoromethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl.
The term "haloalkylcarbonyl" as used herein, refers to a haloalkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
The term "heteroaryl" as used herein, refers to an aromatic monocyclic ring or an aromatic bicyclic ring system. The aromatic monocyclic rings are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S. The five membered aromatic monocyclic rings have two double bonds and the six membered aromatic monocyclic rings have three double bonds. The bicyclic heteroaryl groups are exemplified by a monocyclic heteroaryl ring appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein. Representative examples of heteroaryl include, but are not limited to, benzimidazolyl,_benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indazolyl, indolyl, indolizinyl, isobenzofuranyl, isoindolyl, isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl.
The term "heteroarylalkyl" as used herein, refers to a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. The heteroaryls of this invention may be optionally substituted with 1, 2 or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl, wherein Rf and Rg are independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, haloalkyl, haloalkylcarbonyl and cycloalkylalkyl wherein the cycloalkyl, the cycloalkyl of cycloalkylalkyl as represented by Rf and Rg are each independently unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from the group consisting of halogen, alkyl and haloalkyl. The substituent aryl, the aryl of arylalkyl, the aryl of arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the substituent heteroaryl, the heteroaryl of heteroarylalkyl, the substituent heterocycle, the heterocycle of heterocyclealkyl, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl wherein Rf and Rg are as described above.
The term "heterocycle" as used herein, refers to a non-aromatic monocyclic ring or a non-aromatic bicyclic ring. The non-aromatic monocyclic ring is a three, four, five, six, seven, or eight membered ring containing at least one heteroatom, independently selected from the group consisting of N, O and S. Representative examples of monocyclic ring systems include, but are not limited to, azetidinyl, aziridinyl, diazepinyl, dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl, tetrahydrothienyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1- dioxidothiomorpholinyl (thiomorpholine sulfone) and thiopyranyl. The bicyclic heterocycles are exemplified by a monocyclic heterocycle appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein. Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent atoms of the monocyclic ring are linked by a bridge of between one and three additional atoms selected from the group consisting o f carbon, nitrogen and oxygen. Representative examples of bicyclic ring systems include but are not limited to, for example, benzopyranyl, benzothiopyranyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, 1,5- diazocanyl, 3,9-diaza-bicyclo[4.2.1]non-9-yl, 3,7-diazabicyclo[3.3.1]nonane, octahydro- pyrrolo[3,4-c]pyrrole, indolinyl, isoindolinyl, 2,3,4,5-tetrahydro-lH-benzo[c]azepine, 2,3,4,5-tetrahydro-lH-benzo[ό]azepine, 2,3,4,5-tetrahydro-lH-benzo[d]azepine, tetrahydroisoquinolinyl and tetrahydroquinolinyl. The heterocycles of this invention may be optionally substituted with 1, 2 or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl, wherein Rf and Rg are independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl, haloalkyl, haloalkylcarbonyl and cycloalkylalkyl wherein the cycloalkyl, the cycloalkyl of cycloalkylalkyl as represented by Rf and Rg are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, alkyl and haloalkyl. The substituent aryl, the aryl of arylalkyl, the aryl of arylcarbonyl, the aryi of aryloxy, the aryl of arylsulfonyl, the heteroaryl, the heteroaryl of heteroarylalkyl, the substituent heterocycle, the heterocycle of heterocyclealkyl, the heterocycle of heterocyclecarbonyl, the heterocycle of heterocycleoxy, may be optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl, nitro, RfRgN-, RfRgNalkyl, RfRgNcarbonyl and RfRgNsulfonyl wherein Rf and Rg are as described herein.
The term "heterocyclealkyl" as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of heterocyclealkyl include, but are not limited to, pyridin-3- ylmethyl and 2-pyrimidin-2-ylpropyl.
The term "heterocyclealkoxy" as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein. The term "heterocycleoxy" as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an oxy group, as defined herein. The term "heterocycleoxyalkyl" as used herein, refers to a heterocycleoxy, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
The term "heterocycle-NH-" as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a nitrogen atom.
The term "heterocycle-NH-alkyl" as used herein, refers to a heterocycle-NH-, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
The term "heterocyclecarbonyl" as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of heterocyclecarbonyl include, but are not limited to, 1- piperidinylcarbonyl, 4-morpholinylcarbonyl, pyridin-3-ylcarbonyl and quinolin-3-ylcarbonyl.
The term "heterocyclesulfonyl" as used herein, refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein. Representative examples of heterocyclesulfonyl include, but are not limited to, 1- piperidinylsulfonyl, 4-morpholinylsulfonyl, pyridin-3-ylsulfonyl and quinolin-3-ylsulfonyl.
The term "hydroxy" as used herein, refers to an -OH group.
The term "hydroxyalkyl" as used herein, refers to a hydroxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2- hydroxyethyl, 3-hydroxypropyl and 2-ethyl-4-hydroxyheptyl.
The term "oxo" as used herein, refers to a =0 group.
The term "oxy" as used herein, refers to a -O- group. The term "sulfonyl" as used herein, refers to a -S(O)2- group.
Salts
The present compounds may exist as therapeutically suitable salts. The term "therapeutically suitable salt," refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation and allergic response, commensurate with a reasonable benefit/risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide the salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, form ate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifiuoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like. Basic addition salts may be prepared during the final isolation and purification of the present compounds by reaction of a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine andN,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like, are contemplated as being within the scope of the present invention. Prodrugs
The present compounds may also exist as therapeutically suitable prodrugs. The term "therapeutically suitable prodrug," refers to those prodrugs or zwitterions which are suitable for use in contact with the tissues of patients without undue toxicity, irritation and allergic response, are commensurate with a reasonable benefit/risk ratio and are effective for their intended use. The term "prodrug," refers to compounds that are rapidly transformed in vivo to the parent compounds of formula (I-IXc) for example, by hydrolysis in blood. The term "prodrug," refers to compounds that contain, but are not limited to, substituents known as "therapeutically suitable esters." The term "therapeutically suitable ester," refers to alkoxycarbonyl groups appended to the parent molecule on an available carbon atom. More specifically, a "therapeutically suitable ester," refers to alkoxycarbonyl groups appended to the parent molecule on one or more available aryl, cycloalkyl and/or heterocycle groups as defined herein. Compounds containing therapeutically suitable esters are an example, but are not intended to limit the scope of compounds considered to be prodrugs. Examples of prodrug ester groups include pivaloyloxymethyL acetoxymethyl, phthalidyl, indanyl and methoxymethyl, as well as other such groups known in the art. Other examples of prodrug ester groups are found in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
Optical Isomers-Diastereomers-Geometric Isomers
Asymmetric centers may exist in the present compounds. Individual stereoisomers of the compounds are prepared by synthesis from chiral starting materials or by preparation of racemic mixtures and separation by conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on chiral chromatographic columns. Starting materials of particular stereochemistry are either commercially available or are made by the methods described hereinbelow and resolved by techniques well known in the art.
Geometric isomers may exist in the present compounds. The invention contemplates the various geometric isomers and mixtures thereof resulting from the disposal of substituents around a carbon-carbon double bond, a cycloalkyl group, or a heterocycloalkyl group. Substituents around a carbon-carbon double bond are designated as being of Z or E configuration and substituents around a cycloalkyl or heterocycloalkyl are designated as being of cis or trans configuration. Furthermore, the invention contemplates the various isomers and mixtures thereof resulting from the disposal of substituents around an adamantane ring system. Two substituents around a single ring within an adamantane ring system are designated as being of Z or E relative configuation. For examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. Ie Noble J. Org. Chem. 63: 2758-2760, 1998.
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes and Experimentals that illustrate a means by which the compounds of the invention may be prepared. The compounds of this invention may be prepared by a variety of procedures and synthetic routes. Representative procedures and synthetic routes are shown in, but are not limited to, Schemes 1-18.
Abbreviations which have been used in the descriptions of the Schemes and the Examples that follow are: Cbz for benzyloxycarbonyl; CbzCl for benzyloxycarbonyl chloride; DCE for 1,2-dichloroethane; DCM for dichloromethane; DMAP for dimethylaminopyridine; DME for 1,2-dimethoxy ethane; DMF for N,N-dimethylform amide; DMSO for dimethylsulfoxide; DAST for (diethylamino)sulfur trifluoride; DIPEA for Hϋnig's base for diisopropylethylamine; DMPU for l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)- pyrimidinone; EDCI for (3-dimethylaminopropyl)-3-ethylcarbodiimide HCl; EtOAc for ethyl acetate; Et2O for diethyl ether; EtOH for ethanol; HATU for O-(7-azabenzotriazol-l-yl)-N, N, N', N'-tetramethyluronium hexafluoro-phosphate; HOBt for hydroxybenzotriazole hydrate; iPrOH for isopropyl alcohol; KOTMS for potassium trimethylsilanolate; LAH for lithium aluminum hydride; MeOH for methanol; NMO for N-methylmorpholine iV-oxide; NaOAC for sodium acetate; OXONE for potassium peroxymonosulfate; tBuOK for potassium tert-butoxide; TBTU for O-benzotriazol-l-yl-N,N,iV',iV'-tetramethyluronium tetrafluoroborate; THF for tetrahydrofuran; TosMIC for p-toluenesulfonyhnethyl isocyanide; TPAP for tetrapropylammonium perruthenate; TFAA for trifluoroacetic anhydride; tosyl for para-toluene sulfonyl, mesyl for methane sulfonyl, and triflate for trifluoromethane sulfonyl.
Schemel
Figure imgf000037_0001
(1) (3)
Figure imgf000037_0002
Acids of general formula (2) wherein X = OH can be coupled to substituted adamantamines of general formula (1) with reagents such as EDCI and HOBt to provide amides of general formula (3). Substituted adamantanes of general formula (3), wherein A1, A2, A3, A4, R1, R2, R3, R4, D and E are as defined in formula I, may be prepared as in Scheme 1. Substituted adamantamines of general formula (1), purchased or prepared using methodology known to those in the art, may be treated with acylating agents of general formula (4), wherein X is chloro, bromo, or fluoro, Y is a leaving group such as Br (or a protected or masked leaving group) to provide amides of general formula (5). The substituted amides of general formula (5) may be treated with nucleophiles of general formula (6), wherein J is oxygen or sulfur and a base such as sodium hydride. When J is sulfur that reaction may be followed by oxidation with reagents like Oxone to provide amides of general formula (3) wherein D can become S(O) or S(O)2. In some examples, A , A2, A3 and/or A4 in amines of formula (1) may exist as a group further substituted with a protecting group such as a carboxylic acid protected as the methyl ester. Examples containing a protected functional group may be required due to the synthetic schemes and the reactivity of said groups and could be later removed to provide the desired compound. Such protecting groups can be removed using methodology known to those skilled in the art or as described in T. W. Greene, P. G. M. Wuts "Protective Groups in Organic Synthesis" 3rd ed. 1999, Wiley & Sons, Inc.
Scheme 2
Figure imgf000038_0001
Substituted adamantane amines of general formula (8), wherein A1, A2, A3, A4, R1 and R2 are as defined in formula I, may be prepared as in Scheme 2. Substituted adamantane ketones of general formula (7) can be purchased or prepared using methodology known to those in the art. Ketones of general formula (7) can be treated with ammonia or primary amines (R2NH2) followed by reduction with reagents such as sodium borohydride or H2 over Pd/C in a solvent like methanol to provide amines of general formula (8). In some examples, A1, A2, A3 and/or A4 in ketones of formula (7) may be a functional group substituted with a protecting group such as a carboxylic acid protected as the methyl ester. These protecting groups can be removed using methodology known to those in the art in amines of general formula (8) or in compounds subsequently prepared from ketones of general formula (7) or amines of general formula (8). Scheme 3 carboxylation
Figure imgf000039_0001
Figure imgf000039_0002
Substituted adamantanes of general formula (10), wherein A2, A3 and A4 are as defined in formula I, may be prepared as in Scheme 3. Substituted adamantanes of general formula (9) can be purchased or prepared using methodology known to those skilled in the art. Adamantanes of general formula (9) can be treated with oleum and formic acid followed by an alcohol GOH, where G is an alkyl, cycloalkyl, hydrogen, aryl, or acid protecting group, to provide adamantanes of general formula (10). In some examples, G in formula (10) may be a protecting group such as methyl. These protecting groups can be removed using methodology known to those skilled in the art from adamantanes of general formula (10) or in compounds subsequently prepared from (10).
Scheme 4
Figure imgf000039_0003
Substituted adamantanes of general formula (14), wherein A2, A3, A4, R1, R2, R3, R4, D, E, R16 and R17 are as defined in formula I, may be prepared as in Scheme 4. Adamantyl acids of general formula (11) may be prepared as described herein or using methodology known to those skilled in the art. The acids of general formula (11) may be coupled with amines of general formula (12), wherein R16 and R17 are defined as in formula I, with reagents such as O-(benzotrialzol-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU) to provide amides of general formula (13). In some examples, A2, A3, A4, R1, R2, R3, R16 and R17 in amines of formula (13) may contain a functional group substituted with a protecting group, for example, a carboxy protected as an ester. These protecting groups may be removed using methodology known to those in the art to provide amides of general formula (14).
Scheme 5
Figure imgf000040_0001
18 19 20
Acids of general formulas (17) wherein R3, R4, D and E are as defined in formula (I) can be prepared as shown in Scheme 5. Phenols and thiols of general formula (15) wherein D is -O- or -S-, purchased or prepared using methodology known to those skilled in the art, may be treated with a reagent like l,l,l-trichloro-2-methyl-propan-2-ol (16) in the presence of abase like sodium hydroxide in a solvent like acetone to provide acids of general formula (17).
Esters of general formula (18) wherein P is an acid protecting group such as, but not limited to, C1-C6 alkyl, aryl (substituted or unsubstituted) or arylalkyl (substituted or unsubstituted), may undergo an aromatic substitution or related reaction with halides of formula E-X1 wherein X1 is Cl, Br or I and E is as defined in formula (I), in the presence of a base like sodium hydride in a solvent like DMPU to afford compounds of formula (19). Removal of the acid protecting group, P, provides acids of formula (17). Cleavage of the acid protecting group can be conducted by either acidic or basic hydrolysis when P is C1-C6 alkyl, or hydrogenolyis when P is benzyl.
Alternatively, esters of general formula (18) may be coupled with halides of formula E-X1 wherein X1 is Cl, Br or I and E is aryl or heteroaryl, under with a metal catalyst like palladium along with ligands, to provide compounds of formula (19).
Compounds of formula (19) can also be obtained from the reaction of bromoesters of general formula (20), with compounds of formula (15) wherein D is -O- or -S-and E is defined as in formula (I), in the presence of a base such as, but not limited to, potassium carbonate, to provide esters of general formula (19).
Scheme 6
Figure imgf000041_0001
Substituted adamantane amides of general formula (21), wherein Rf and Rg are independently selected from the group consisting of hydrogen, alkyl, alkoxyalkyl, alkylsulfonyl, cycloalkyl, and cycloalkylalkyl wherein the cycloalkyl, the cycloalkyl of cycloalkylalkyl as represented by Rf and Rg are each independently unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of alkyl, halogen, and haloalkyl, Z is alkyl, aryl, heteroaryl, cycloalkyl, heterocycle, arylalkyl, heteroarylalkyl or heterocyclealkyl, and A2, A3, A4, R1 , R2, R3, R4, R18, R2, D and E are as defined in formula (I), can be prepared as shown in Scheme 6. .
Adamantane acids of general formula (20) can be coupled with amines of formula RfRgNH, in the presence of a coupling agent such as, but not limited to, TBTU, and a base such as, but not limited, to diisopropylethylamine. The reaction is generally performed in a solvent such as, but not limited to, DMF, at a temperature of about room temperature to about 50 0C to provide amides of general formula (21).
Scheme 7
Figure imgf000042_0001
Substituted adamantanes of general formula (25), (26), and (27), wherein A2, A3, A4, R1, R2, R3, R4, D and E are as defined in formula I, can be prepared as shown in Scheme 7. Adamantanes of general formula (22) wherein P is hydrogen or an acid protecting group such as, but not limited to, C1-C6 alkyl, aryl (substituted or unsubstituted) or arylalkyl (substituted or unsubstituted), can be converted to aldehydes of formula (23) by (a) treatment with a reducing agent such as, but not limited to, lithium aluminum hydride, in a solvent like THF; and (b) treating the product from step (a) with an oxiding agent such as, but not limited to, TPAP, in the presence of NMO, and in a solvent like dichloroethane.
Adamantane aldehydes of general formula (23) can be treated with TosMIC and a base like t-BuOK in a solvent mixture like DME and ethanol to provide nitriles of general formula (24). Nitriles of general formula (24) can be hydrolyzed with potassium hydroxide in a solvent like ethylene glycol to provide acids of general formula (25). When treated with hydrogen peroxide and sodium hydroxide in a solvent mixture like methanol and DMSO, nitriles of general formula (24) can be transformed to amides of formula (26).
Tetrazoles of formula (27) can be prepared from adamantanes of general formula (24) when treated with reagents like sodium azide and zinc bromide in a solvent like water and isopropanol. Scheme 8
Figure imgf000043_0001
31 32 33
Substituted adamantanes of general formula (30), wherein A2, A3, A4, R1, R2, R3, R4,
D and E are as defined in formula (I), can be prepared as shown in Scheme 8.
Substituted adamantanes of general formula (28) can be dehydrated with a reagent like TBTU in the presence of a base like isopropylethylamine in a solvent like N,N- dimethylacetamide to provide nitriles of general formula (29). Nitriles of general formula (29) can be treated with reagents like trimethyl tin chloride and sodium azide in a solvent like toluene to provide tetrazoles of general formula (30).
Alternatively, adamantane amines of general formula (31) wherein P is hydrogen or C1-C6 alkyl, can be (a) treated with a reagent like CbzCl in a solvent like dichloromethane in the presence of a base like diisopropylethylamine; (b) treating the resulting product with a reagent like KOTMS in a solvent like THF; and (c) treating the acid from step (b) with ammonia or ammonium hydroxide in the presence of a reagent like EDCI and HOBt, and a base like diisopropylethylamine, in a solvent like DMF, to yield adamantane amides of general formula (32) wherein P is a protecting group like -C(O)OCH2C6Hs. The amides of general formula (32) can be (a) treated with a reagent like trifluoroacetic anhydride in a solvent like dichloromethane in the presence of a base like triethylamine; and (b) treating the intermediate from step (a) with a catalyst like Pd(OH)2 on carbon under an atmosphere of hydrogen, to provide amines of formula (33). Amines of general formula (33) can be coupled to acids of general formula (17), in the presence of a reagent like HATU and a base like diisopropylethylamine, in a solvent like DMF, to provide compounds of general formula (29). Scheme 9
Figure imgf000044_0001
Substituted adamantanes of general formula (34), wherein A2, A3, A4, R1, R2, R3, R4, D and E are as defined in formula I, can be prepared from treatment of compounds of formula (29) with hydroxylamine hydrochloride in a solvent like DMSO, in the presence of a base like diisopropylethylamine.
Scheme 10
substitution oxidation
Figure imgf000044_0002
Figure imgf000044_0003
Figure imgf000044_0004
Substituted adamantanes of general formula (37) and (38), wherein A2, A3, A4, R1, R2, R3, R4, D and E are as defined in formula I, and R101 is alkyl, cycloalkyl, aryl, heteroaryl, or heterocycle, can be prepared as shown in Scheme 10.
Substituted adamantanes of general formula (35) can be (a) treated with trifluoroacetic anhydride in a solvent like trifluoroacetic acid; and (b) treating the product of step (a) with a thiol of formula R101SH at elevated temperature, typically at about 120 0C for a period of about 20 hours, in a solvent like trifluoroacetic acid to provide thioethers of general formula (36). Thioethers of general formula (36) can be oxidized with an oxidizing agent such as, but not limited to, 3-chloroperbenzoic acid, in a solvent such as, but not limited to, dichloromethane, to provide sulfoxides of general formula (37) and/or sulfones of general formula (38). Scheme 11
Figure imgf000045_0001
Figure imgf000045_0002
Substituted adamantanes of general formula (42), wherein A2, A3, A4, R1, R2, R3, R4, R25, R26, D and E are as defined in formula (I), can be prepared as shown in Scheme 11. Substituted adamantanes of general formula (22) wherein P is hydrogen or an acid protecting group such as, but not limited to, C1-C6 alkyl, aryl (substituted or unsubstituted) or arylalkyl (substituted or unsubstituted), can be converted alcohols of formula (39) by treatment with a reducing agent such as, but not limited to, lithium aluminum hydride or diisobutylaluminum hydride in a solvent like THF. Reaction of the alcohols of general formula (39) with trifluoromethanesulfonic anhydride in the presence of a base like pyridine and in a solvent like dichloromethane provides the intermediate triflate that can be isolated. Treatment of the triflate with potassium thioacetate in a solvent like dimethylformamide yields adamantanes of general formula (40). Adamantane thioacetates of general formula (40), when treated with an oxidizing agent such as, but not limited to, hydrogen peroxide and a base like sodium acetate in a solvent like acetic acid provides sulfonic acids of general formula (41).
Sulfonic acids of general formula (41) can be coupled with an amine of formula R25R26NH wherein R25 and R26 are defined as in formula I to provide compounds of formula (42). Numerous reaction conditions for such a conversion are known to one skilled in the art. One such coupling utilizes triphosgene in the presence of a base like triethylarnine with a catalytic amount of dimethylformamide in a solvent like dichloromethane, followed by the addition an amine of formula R25R26NH.
Compounds of formula (42) wherein R25 is as defined in formula (I) other than hydrogen and R26 is hydrogen, or R25 and R26 are as defined in formula (I) other than hydrogen, can also be obtained from the mono or dialkylation of compounds of formula (42) wherein R25 and R26 are hydrogen.
The mono alkylation can be facilitated with an alkylating reagent of formula R25X1 wherein R25 is methyl, benzyl, and allyl, and X1 is a leaving group such as, but not limited to, Cl, Br, I, triflate or tosylate. The reaction is generally conducted in the presence of a base such as, but not limited to, alkali metal carbonates (for example, cesium carbonate and the like), in a solvent such as, but not limited to, DMF, providing compounds of formula (42) wherein R25 is methyl, benzyl, and allyl, and R26 is hydrogen. Further alkylation with R26X1 wherein R26 is methyl, benzyl, and allyl and X1 as defined above, using the aforementioned reaction condition, affords compounds of formula (42) wherein R25 and R26 are independently selected from the group consisting of methyl, benzyl, and allyl. The reaction can be conducted stepwise or in situ without isolating the product of the monoalkylation.
Alternatively, compounds of formula (42) wherein R and R are identical and are as defined in formula (I) other than hydrogen, can be prepared from the reaction of compounds of formula (42) wherein R25 and R26 are hydrogen and about two equivalents of the alkylating agent.
Scheme 12 amide carbonylation formation
Figure imgf000046_0002
Figure imgf000046_0001
Figure imgf000046_0003
Substituted adamantanes of general formula (46), wherein A2, A3, A4, R1, R2, R3, R4, R16, R17, D and E are as defined in formula (I) can be prepared as shown in Scheme 12. Substituted adamantanes of general formula (43) can be carbonylated with formic acid and oleum and poured into a solution of formula R15OH to provide an adamantane of general formula (44) wherein R15 is as defined in formula (I). Adamantanes of general formula (44) wherein R15 is not hydrogen can be converted to admantanes of formula (44) wherein R15 is hydrogen using methodologies listed in T. W. Greene, P. G. M. Wuts "Protective Groups in Organic Synthesis" 3rd ed. 1999, Wiley & Sons, hie. The resulting acids can be coupled to amines of general formula R16R17NH to provide amides of formula (45) in the presence of coupling reagents such as, but not limited to, EDCI and HOBt in a solvent like dichloromethane. Adamantanes of general formula (45) may be treated with alcohols or thiols of general formula (15) wherein D is — O- or — S— and E is defined as in formula (I), in the presence of a base like potassium carbonate in a solvent like toluene to provide adamantanes of general formula (46).
Adamantanes of general formula (46) wherein D is -S- can be converted to compounds of formula (46) wherein D is -S(O)- or -S(O)2- by reacting with an oxidizing agent such as, but not limited to, oxone in a solvent like methanol.
Scheme 13
Figure imgf000047_0001
47 48 49
Figure imgf000047_0002
53 52 51
Substituted adamantanes of general formula (54), wherein A2, A3, A4, R25 and R26 are as defined in formula I, may be prepared as shown in Scheme 13.
Substituted adamantanes of general formula (47) can be brominated with a reagent like hydrobromic acid in a solvent like water to provide bromides of general formula (48). Adamantanes of general formula (48) when treated with ethylene glycol and a catalytic amount of an acid like p-toluenesulfonic acid in a solvent like benzene provide adamantanes of general formula (49). Bromides of general formula (49) can be (a) treated with Rieke zinc in a solvent like tetrahydrofuran; and (b) followed by treatment with reagent (50) (prepared as described in Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Senanayake, C. H. J. Am. Chem. Soc. 2002, 124, 7880-7881) in a solvent like tetrahydrofuran to provide adamantanes of general formula (51). Adamantanes of general formula (51) may be treated with lithium amide of formula LiNHR25R26 (prepared in situ by reacting ammonia with lithium or amines of formula R25R26NH wherein R25 and R26 are other than hydrogen, with t-butyl lithium) in a solvent mixture like ammonia and tetrahydrofuran. The resulting sulfanamides can be oxidized with a reagent like osmium tetroxide with a catalyst oxidant like NMO in a solvent like tetrahydrofuran to provide sulfonamides of general formula (52). Adamantanes of general formula (52) can be deketalized with reagents like hydrochloric acid in a solvent like water and tetrahydrofuran to provide ketones of formula (53). Ketones of formula (53) can be treated with amines of formula R25R26NH followed by reduction with reducing reagents such as, but not limited to, sodium borohydride or hydrogen over Pd/C in a solvent like methanol to provide amines of general formula (54).
Scheme 14
Figure imgf000048_0001
1 (Y)
Substituted adamantanes of general formula (55), (56) and (57) wherein R is hydrogen, alkyl or aryl, and A2, A3, A4, R1, R2, R3, R4, R23, R24, D and E are as defined in formula (I), can be prepared as shown in Scheme 14.
Substituted adamantanes of general formula (23) can be treated with reagents like ammonia and glyoxal in a solvent like water to provide imidazoles of general formula (55). Reaction of compounds of formula (23) with Wittig reagent such as, but not limited to, triethyl phosphonoacetate and a base like sodium hydride in a solvent like dimethoxyethane provides esters of general formula (56) wherein R102 is alkyl or aryl. Esters of general formula (56) can be cleaved with lithium hydroxide in a solvent mixture like tetrahydrofuran and water to provide acids of general formula (56) wherein R102 is hydrogen.
Adamantanes of general formula (23) can be reductively animated with amines of general formula R23R24NH with a reagent like sodium triacetoxyborohydride in the presence of an acid like acetic acid in a solvent like dichloroethane to yield amines of general formula (57).
Scheme 15 - oxidation
Figure imgf000049_0001
heterocycle formation
Figure imgf000049_0002
Figure imgf000049_0003
Substituted adamantanes of general formula (60), wherein A2, A3, A4, R1, R2, R3, R4, D and E are as defined in formula I and Q is hydrogen, alkyl, or cycloalkyl, can be prepared as shown in Scheme 15. Substituted adamantanes of general formula (23) can be treated with a reagent like acetylenemagnesium chloride in a solvent like THF to yield alcohols of general formula (58). Adamantane alcohols of general formula (58) can be oxidized with a reagent like Dess- Martin periodinane in a solvent like dichloromethane to provide alkynones of general formula (59). Alkynones of general formula (59) can be reacted with a reagent like hydroxylamine hydrochloride in the presence of a base like potassium carbonate in a solvent like isopropanol to provide heterocycles of general formula (60).
Scheme 16
Figure imgf000050_0001
Substituted adamantanes of general formula (61), wherein A2, A3, A4, R1, R2, R3, R4, R ,2z0υ, D and E are as defined in formula (I), can be prepared as shown in Scheme 16.
Adamantanes of general formula (39) can be alkylated with a reagent of formula R20X1, wherein X1 is a halide or other leaving group like bromide, iodide, tosylate or triflate, in the presence of a base like sodium hydride in a solvent like dimethylformamide to yield ethers of general formula (61).
Scheme 17
Figure imgf000050_0002
Substituted adamantanes of general formula (63), wherein E is aryl or heteroaryl and
A1, A2, A3, A4, R1, R2, R3, R4, and D are as defined in formula (I) and R103 and R104 are alkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocycle, heteroaryl, heteroarylalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, or heterocyclealkyl, or R103 and R104 combined to the atom to which they are attached form a heterocycle or heteroaryl can be prepared as shown in Scheme 17.
Substituted adamantanes of general formula (62) wherein X1 is a halide or triflate can be coupled with amines of formula IStHR103R10 with a reagent combination like copper iodide and N,N-dimethylglycine in a solvent like DMSO under microwave heating to provide adamantanes of general formula (63). Scheme 18
Figure imgf000050_0003
Substituted adamantanes of general formula (65), wherein m is 1 or 2, A1, A2, A3, A4, R1, R2, R3, R4 and D are as defined in formula (I), E is aryl or heteroaryl, and X2 is halogen, can be prepared as shown in Scheme 18.
Adamantanes of general formula (64) can be halogenated with a reagent like N- bromosuccinimde in the presence of an acid like HBr in a solvent like dichloromethane to yield aryl halides of general formula (65).
It is understoond that the schemes described herein are for illustrative purposes and that routine experimentation, including appropriate manipulation of the sequence of the synthetic route, protection of any chemical functionality that are not compatible with the reaction conditions and deprotection are included in the scope of the invention. Protection and Deprotection of carboxylic acids and amines are known to one skilled in the art and references can be found in "Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, 3rd edition, 1999, Wiley & Sons, hie.
The compounds and processes of the present invention will be better understood by reference to the following Examples, which are intended as an illustration of and not a limitation upon the scope of the invention. Further, all citations herein are incorporated by reference.
Compounds of the invention were named by ACD/ChemSketch version 5.01 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or were given names consistent with ACD nomenclature. Adamantane ring system isomers were named according to common conventions. Two substituents around a single ring within an adamantane ring system are designated as being of Z or E relative configuation (for examples see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. Ie Noble J. Org. Chem. 63: 2758-2760, 1998).
Example 1
E-4-(2-methyl-2-phenoxy-propionylamino V adamantane- 1 -carboxylic acid amide
Example IA
E- and Z- 5-hydroxy-2-adamantamine A solution of 5-hydroxy-2-adamantanone (10 g, 60.161mmoles) and 4A molecular sieves (5 g) in methanolic ammonia (7N, 100 mL) was stirred overnight at room temperature. The mixture was cooled in an ice bath, treated by the portionwise addition of sodium borohydride (9.1 g, 240.64 mmoles) and stirred at room temperature for 2 hours. The mixture was filtered and MeOH was removed under reduced pressure. The mixture was taken into DCM (100 mL), acidified with IN HCl to pH = 3 and the layers separated. The aqueous layer was treated with 2N NaOH solution to pH = 12 and extracted three times with 4:1 THF:DCM. The combined organic extracts were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as a white solid (9.84 g, 97.9%).
Example IB E-2-bromo-N-r5-hvdroxy-adamantan-2-ylV2-methyl-propionamide
A solution of E- and Z-5-hydroxy-2-adamantamine (0.868g, 5.2 mmoles) in DCM (15.0 mL) and DIPΕA (2.5 mL) was cooled in an ice bath and treated with 2-bromoisobutyryl bromide (0.72 mL, 5.8 mmoles) in DCM (2.5 mL). The mixture was stirred for 2 hours at room temperature and DCM was removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as dark beige solid (1.17 g, 71%). The isomers were separated by column chromatography (silica gel, 5-35% acetone in hexane) to furnish 0.78 g of E-2-bromo-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide and 0.39 g of Z-2-bromo-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide.
Example 1C
E-4-(2-bromo-2-methyl-propionylamino)-adamantane-l-carboxylic acid methyl ester A solution of E- 2-bromo-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide (0.78 g, 2.48mmol) in 99% formic acid (2.5 mL) was added dropwise with vigorous gas evolution over 10 minutes to a rapidly stirred 30% oleum solution (7.5 mL) heated to 60 0C (W. J. Ie Noble, S. Srivastava, C. K. Cheung, J. Org. Chem. 48: 1099-1101, 1983). Upon completion of addition, more 99% formic acid (2.5 mL) was slowly added over the next 10 minutes. The mixture was stirred another 60 minutes at 60 0C and then slowly poured into vigorously stirred iced water (30.0 mL) cooled to 0 0C. The mixture was allowed to slowly warm to 23 0C, filtered and washed with water to neutral pH (100 mL). The precipitate was dried in a vacuum oven, taken into MeOH and treated with thionyl chloride at O0C (0.2 mL, 2.8 mmoles). The reaction mixture was stirred at room temperature for 3 hours and then MeOH was evaporated under reduced pressure to provide the title compound as an off-white solid.
Example ID E-4-(2-methyl-2-phenoxy-propionylaminoVadamantane- 1 -carboxylic acid
Step A
A solution of phenol (20.7 mg, 0.22 mmoles) and sodium hydride (60%, 10.8 mg, 0.27 mmoles) in toluene (2 mL) was stirred at room temperature for 1 hour. ThenE-4-(2- bromo-2-methyl-propionylamino)-adamantane-l-carboxylic acid methyl ester (71.6 mg, 0.2 mmoles) was added and the resulting mixture was shaken at 1000C for 48 hours. After that the reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to provide crude methyl ester of the title compound that was purified on reverse phase HPLC. Step B The methyl ester of the title compound obtained from step A was hydrolyzed with 2N aqueous NaOH, THF and ethanol (2:1:1, 2 mL) at room temperature overnight. The reaction mixture was acidified with IN HCl and extracted with ethyl acetate. The organic layer was separated, washed with water and brine respectively, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound.
Example IE
E-4-(2-methyl-2-phenoxy-propionylaminoy adamantane- 1 -carboxylic acid amide A solution of E-4-(2-methyl-2-phenoxy-propionylamino)-adamantane-l -carboxylic acid (23 mg, 0.064 mmoles) in DCM (2 mL) was treated with HOBt (9.5 mg, 0.07 mmoles) and ΕDCI (14.7 mg, 0.077 mmoles) and stirred at room temperature for 1 hour. Excess of aqueous (30%) ammonia (2 mL) was added and the reaction was stirred for additional 20 hours. The layers were separated and the aqueous layer extracted twice more with methylene chloride (2x2 mL). The combined organic extracts were washed with water (3x2 mL), brine (2 mL), dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the crude title compound that was purified on reverse phase HPLC to provide the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 7.26 - 7.31 (m, 2 H) 7.25 (d, J=7.49 Hz, 1 H) 7.02 (t, J=7.33 Hz, 1 H) 6.95 (s, 1 H) 6.91 (d, J=7.80 Hz, 2 H) 6.68 (s, 1 H) 3.79 - 3.88 (m, 1 H) 1.91 (s, 2 H) 1.76 - 1.87 (m, 5 H) 1.71 (s, 2 H) 1.65 (d, J=12.79 Hz, 2 H) 1.45 (s, 6 H) 1.38 (d, J=12.79 Hz, 2 H). MS (ESI+) m/z 357 (M+H)+.
Example 2 E-4-[2-methyl-2-(4-(trifluoromethyl-benzyloxy)-propionylaminol-adamantaiie-l-carboxylic acid amide
The title compound was prepared according to the procedure outlined in Example ID and IE substituting 4-(trifluoromethyl)benzyl alcohol for phenol. 1H NMR (500 MHz,
DMSO-D6) δ ppm 7.73 (d, J=SAl Hz5 2 H) 7.62 (d, J=8.11 Hz, 2 H) 7.07 (d, J=7.49 Hz, 1 H) 6.95 (s, 1 H) 6.68 (s, 1 H) 4.60 (s, 2 H) 3.78 (d, J=7.49 Hz, 1 H) 1.88 (s, 2 H) 1.76 - 1.85 (m, 5 H) 1.72 (s, 2 H) 1.59 (d, J=UAO Hz, 2 H) 1.39 - 1.44 (m, 8 H). MS (ESI+) m/z 439 (M+H)+
Example 3
E-4-[2-methyl-2-(2-methyl-cyclohexyloxyVpropionylamino]-adamantane-l-carboxylic acid A two phase suspension of E-4-(2-bromo-2-methyl-propionylamino)-adamantane-l- carboxylic acid methyl ester (71.6 mg, 0.2 mmoles), 2-methylcyclohexanol (0.033 mL, 0.24 mmoles) and tetrabutylammonium bromide (6 mg, 0.02 mmoles) in DCM (1.0 mL) and 50% aqueous NaOH (1.0 mL) was stirred at room temperature for 20 hours. After that the reaction mixture was diluted with DCM, neutralized with 3N HCl and layers separated. Organic layer was washed with water (3x2 mL), dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide crude methyl ester of the title compound that was purified on reverse phase HPLC and hydrolyzed with 2N aqueous NaOH, THF and ethanol (2:1:1, 2 mL) at room temperature for 20 hours. The reaction mixture was acidified with IN HCl and extracted with ethyl acetate. The organic layer was separated, washed with water and brine respectively, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound. 1H NMR (400 MHz, DMSO-D6) δ ppm 11.77 - 12.49 (m, 1 H) 7.27 (d, J=7.98 Hz, 1 H) 3.76 (d, J=6.75 Hz, 1 H) 3.19 - 3.28 (m, 1 H) 0.98 - 1.96 (m, 28 H) 0.85 - 0.96 (m, 3 H) MS (ESl+) m/z 378 (M+H)+ Example 4 E-A- [2-methyl-2-(3 -methyl-c vclohexyloxyVpropionylaminoi -adamantane- 1 -carboxylic acid
The title compound was prepared according to the procedure outlined in Example 3 substituting 3-methylcyclohexanol for 2-methylcyclohexanol. 1H NMR (400 MHz, DMSO- D6) δ ppm 11.70 - 12.38 (m, 1 H) 7.16 (d, J=7.36 Hz, 1 H) 3.76 (s, 1 H) 3.41 - 3.53 (m, 1 H) 1.33 - 1.96 (m, 18 H) 1.05 - 1.31 (m, 8 H) 0.66 - 0.99 (m, 5 H). MS (ESI+) m/z 378 (M+H)+
Example 5 E-4-(2-cycloheptyloxy-2-methyl-propionylaminoVadamantane- 1 -carboxylic acid
The title compound was prepared according to the procedure outlined in Example 3 substituting cycloheptanol for 2-methylcyclohexanol. 1H NMR (400 MHz, DMSO-D6) δ ppm 11.85 - 12.35 (m, 1 H) 7.21 (d, J=7.67 Hz, 1 H) 3.70 - 3.88 (m, 2 H) 1.37 - 1.96 (m, 25 H) 1.27 (s, 6 H). MS (ESI+) m/z 378 (M+H)+
Example 6
E-4-(2-(cyclohexylmethoxy-2-methyl-propionylaminoVadamantane-l-carboxylic acid The title compound was prepared according to the procedure outlined in Example 3 substituting cyclohexylmethanol for 2-methylcyclohexanol. 1H NMR (400 MHz, DMSO-D6) δ ppm 11.70 - 12.50 (m, 1 H) 7.06 (d, J=7.36 Hz5 1 H) 3.76 (d, J=7.98 Hz, 1 H) 3.19 (d,
J=6.14 Hz, 2 H) 1.41 - 1.95 (m, 19 H) 1.26 (s, 6 H) 0.90 - 1.25 (m, 5 H). MS (ESI+) m/z 378 (M+H)+
Example 7 E-4-[2-(4-chloro-phenoxyV2-methyl-propionylammo]-adamantane-l-carboxylic acid
Example 7A
E-4-Amino-adamantane- 1 -carboxylic acid
To 1.0 g (10 wt%) of 5% Pd/C is added 4-oxo-adamantane-l -carboxylic acid (10.0 g, 51.5 mmol) followed by 7M NH3 in MeOH (200 niL). The reaction mixture is stirred under an atmosphere of H2 at 23 0C for 16-24 hours; water (200 mL) is added; and the catalyst is removed by filtration. The catalyst is washed with methanol and the filtrate solution is concentrated under reduced pressure at a bath temperature of 35 0C until solvent stops coming over. Approximately 150 mL of a slurry remains. Acetonitrile (300 mL) is added to the slurry which is then stirred for 3 hours at 23 0C. The slurry is filtered and washed once with acetonitrile (100 mL). The wet cake is dried at 50 0C and 20 mmHg under N2 to yield E-4-amino-adamantane-l-carboxylic acid (8.65 g, 86%, 13.1:1.0 E:Z ratio by 1H-NMR m D2O).
Example 7B E-4-Amino-adamantane-l-carboxylic acid methyl ester Methanol (85 mL) was cooled to 00C; acetyl chloride (15.5 mL) was added dropwise; and then the solution was warmed to 23 0C for 15-20 minutes. E-4-Amino-adamantane-l- carboxylic acid (8.53 g, 43.7 mmol) was added and the reaction solution was heated to 45 0C for 16 hours. The reaction solution was cooled to 23 0C and acetonitrile (85 mL) was added. The reaction solution was concentrated under reduced pressure to ~l/4 volume. The reaction solution was further chase distilled with acetonitrile (2x85 mL). The resulting suspension was cooled to 23 0C and filtered. The filtrate was recirculated twice to wash the wet cake. The product was dried at 50 0C, 20 mmHg for 16 hours to afford E-4-amino-adamantane-l- carboxylic acid methyl ester as a white crystalline solid (10.02 g, 93%).
Example 7C
E-4-[2-(4-chloro-phenoxy)-2-methyl-propionylamino]-adamantane-l-carboxylic acid To the solution of E-4-Adamantamine -1-carboxylic acid methyl ester (49 mg, 0.2 mmoles) and triethylamine (0.097 mL, 0.7 mmoles) in DCM (1.0 mL) was added a solution of 2-(4-chlorophenoxy)-2-methylpropionyl chloride (55 mg, 0.24 mmoles) in DCM (1.0 mL). The resulting reaction mixture was stirred at room temperature for 20 hours and concentrated under reduced pressure. The residue was partitioned between ethylacetate and water. The organic layer was separated and washed with IN HCl, water and brine, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the crude methyl ester of the title compound that was purified on reverse phase HPLC and hydrolyzed with 2N aqueous NaOH, THF and ethanol (2:1:1, 2 mL) at room temperature for 20 hours. The reaction mixture was acidified with IN HCl and extracted with ethyl acetate. The organic layer was separated, washed with water and brine respectively, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 11.94 - 12.25 (m, 1 H) 7.30 - 7.36 (m, 3 H) 6.87 - 6.94 (m, 2 H) 3.80 - 3.87 (m, 1 H) 1.93 (s, 2 H) 1.85 (d, J=2.44 Hz, 3 H) 1.80 (d, J=2.75 Hz, 2 H) 1.75 (s, 2 H) 1.68 (d, J=12.82 Hz, 2 H) 1.46 (s, 6 H) 1.38 (d, J=12.82 Hz, 2 H). MS (ESI+) m/z 392 (M+H)+
Example 8
E-4-[2-(4-chloro-phenoxy)-2-methyl-propionylammo]-adamantane-l-carboxylic acid amide The title compound was prepared according to the procedure outlined in Example IE from E-4-[2-(4-chloro-phenoxy)-2-methyl-propionylamino]-adamantane-l-carboxylic acid (Example 7C). 1H NMR (400 MHz, DMSO-D6) δ ppm 7.25 - 7.36 (m, 3 H) 6.94 - 6.99 (m, 1 H) 6.89 - 6.94 (m, 2 H) 6.69 (s, 1 H) 3.83 (d, J=7.67 Hz, 1 H) 1.91 (s, 2 H) 1.75 - 1.87 (m, 5 H) 1.63 - 1.73 (m, 4 H) 1.46 (s, 6 H) 1.32 - 1.42 (m, 2 H). MS (ESl+) m/z 391 (M+H)+
Example 9 E-4-[2-methyl-2-(4-methyl-cyclohexyloxyVpropionylaminol -adamantane- 1 -carboxylic acid. amide
The title compound was prepared according to the procedures outlined in Example 3 and IE, substituting 4-methylcyclohexanol for 2-methylcyclohexanol. 1H NMR (400 MHz, DMSO-D6) δ ppm 7.14 (d, 1 H) 6.98 (s, 1 H) 6.70 (s, 1 H) 3.72 - 3.82 (m, 1 H) 3.39 - 3.50 (m, 1 H) 1.19 - 1.96 (m, 26 H) 0.91 - 1.05 (m, 2 H) 0.81 - 0.89 (m, 3 H). MS (ESI+) m/z 377 (M+H)+.
Example 10
E-4-[(2-phenoxypropanoyDamino] adamantane- 1 -carboxamide The title compound was prepared according to the procedure outlined in Example 7C and IE substituting 2-phenoxy-propionyl chloride for 2-(4-chlorophenoxy)-2- methylpropionyl chloride. 1H NMR (400 MHz, DMSO-D6) δ ppm 7.74 (d, J=7.36 Hz, 1 H) 7.26 (t, J=7.98 Hz, 2 H) 6.83 - 6.99 (m, 4 H) 6.68 (s, 1 H) 4.86 (q, J=6.55 Hz, 1 H) 3.78 (d, J=7.06 Hz, 1 H) 1.69 - 1.92 (m, 11 H) 1.43 (d, J=6.44 Hz, 3 H) 1.37 (d, J=12.89 Hz, 2 H). MS (ESI+) m/z 343 (M+H)+ Example 11 E-4-{r2-methyl-2-(2-methylph.enoxy)propanoyl]ammo>adamantane-l-carboxylic acid.
The title compound was prepared according to the procedure outlined in Example ID substituting 2-methylphenol for phenol. 1H NMR (500 MHz, DMSO-D6) δ ppm 11.58 -
12.61 (br. s, 1 H) 7.28 (d, J=7.32 Hz, 1 H) 7.19 (d, J=7.32 Hz, 1 H) 7.05 - 7.13 (m, 1 H) 6.91 (t, J=6.87 Hz, 1 H) 6.82 (d, J=7.93 Hz, 1 H) 3.79 - 3.88 (m, 1 H) 2.22 (s, 3 H) 1.95 (s, 2 H) 1.86 (d, J=2.75 Hz, 3 H) 1.82 (s, 2 H) 1.76 (s, 2 H) 1.68 (d, J=13.12 Hz, 2 H) 1.46 (s, 6 H) 1.43 (d, J=13.73 Hz, 2 H). MS (ESI+) m/z 372 (M+H)+
Example 12 E-4-{[2-methyl-2-(4-methylphenoxy)propanoyl]amino>adamantane-l-carboxylic acid
The title compound was prepared according to the procedure outlined in Example ID substituting 4-methylphenol for phenol. 1H NMR (500 MHz, DMSO-D6) δ ppm 11.75 - 12.46 (br.s, 1 H) 7.30 (d, J=7.32 Hz, 1 H) 7.08 (d, J=8.24 Hz, 2 H) 6.81 (d, J=8.54 Hz, 2 H)
3.80 - 3.86 (m, 1 H) 2.23 (s, 3 H) 1.94 (s, 2 H) 1.86 (d, J=2.44 Hz, 3 H) 1.82 (s, 2 H) 1.76 (s, 2 H) 1.69 (d, J=12.82 Hz, 2 H) 1.38 - 1.45 (m, 8 H). MS (ESI+) m/z 372 (M+H)+
Example 13 E-A- { [2-(2-chlorophenoxy)-2-metriylpropano yl] amino I adamantane- 1 -carbox ylic acid
The title compound was prepared according to the procedure outlined in Example ID substituting 2-chlorophenol for phenol. 1H NMR (500 MHz, DMSO-D6) δ ppm 11.50 - 12.76 (br. s, 1 H) 7.63 (d, J=7.63 Hz, 1 H) 7.57 (dd, J=7.93, 1.53 Hz, 1 H) 7.36 (t, 1 H) 7.24 (dd, J=8.24, 1.22 Hz, 1 H) 7.16 (t, 1 H) 3.88 - 3.98 (m, 1 H) 2.04 (s, 2 H) 1.94 (d, J=2.44 Hz, 5 H) 1.82 - 1.88 (m, 4 H) 1.52 - 1.59 (m, 8 H). MS (ESI+) m/z 392 (M+H)+
Example 14 E-4-{[2-r2-methoxyphenoxy')-2-methylpropanoyllaminoladamantane-l-carboxamide
The title compound was prepared according to the procedure outlined in Example ID and IE substituting 2-methoxyphenol for phenol. 1H NMR (400 MHz, DMSO-D6) δ ppm 7.91 (d, J=7.67 Hz, 1 H) 7.05 - 7.11 (m, 3 H) 7.00 (s, 1 H) 6.86 - 6.93 (m5 1 H) 6.71 (s, 1 H)
3.81 - 3.88 (m, 1 H) 3.79 (s, 3 H) 1.96 (s, 2 H) 1.76 - 1.92 (m, 9 H) 1.54 (d, J=13.20 Hz, 2 H) 1.36 (s, 6 H). MS (ESI+) m/z 387 (MH-H)+
Example 15
E-4-{[2-(4-methoxyphenoxyV2-metliylpropanoyl'|amino>adamantane-l-carboxamide The title compound was prepared according to the procedure outlined in Example ID and IE substituting 4-methoxyphenol for phenol. 1H NMR (400 MHz, DMSO-D6) δ ppm 7.30 (d, J=7.36 Hz, 1 H) 6.93 - 7.01 (m, 1 H) 6.82 - 6.92 (m, 4 H) 6.70 (s, 1 H) 3.85 (d, J=7.06 Hz, 1 H) 3.71 (s, 3 H) 1.92 - 1.97 (m, 2 H) 1.77 - 1.89 (m, 5 H) 1.74 (s, 3 H) 1.71 (s, 1 H) 1.44 (d, J=12.58 Hz, 2 H) 1.37 (s, 6 H). MS (ESI+) m/z 387 (M+H)+
Example 16
E-4-({2-methyl-2-[3-rtrifluoromethvDphenoxy1propanoyllammo)adamantane-l-carboxamide The title compound was prepared according to the procedure outlined in Example ID and IE substituting 3-trifluoromethylphenol for phenol. 1H NMR (400 MHz, DMSO-D6) δ ppm 7.53 (t, J=7.98 Hz, 1 H) 7.37 (dd, J=12.12, 7.21 Hz, 2 H) 7.19 (dd, 1 H) 7.14 (s, 1 H) 6.95 (s, 1 H) 6.68 (s, 1 H) 3.81 (s, 1 H) 1.90 (s, 2 H) 1.80 (d, J=7.67 Hz, 4 H) 1.76 (s, 1 H) 1.70 (s, 2 H) 1.61 (d, 2 H) 1.52 (s, 6 H) 1.32 (d, J=I 3.50 Hz, 2 H). MS (ESI+) m/z 425 (M+H)+
Example 17 E-4- { [2-(3 -methoxyphenoxyV2-methylpropanoyll amino ) adamantane- 1 -carboxamide
The title compound was prepared according to the procedure outlined in Example ID and IE substituting 3-methoxyphenol for phenol. 1H NMR (500 MHz, DMSO-D6) δ ppm 7.26 (d, J=7.32 Hz, 1 H) 7.17 (t, J=8.24 Hz, 1 H) 6.98 (s, 1 H) 6.71 (s, 1 H) 6.60 (dd, J=8.39, 1.98 Hz, 1 H) 6.43 - 6.48 (m, 2 H) 3.82 (d, J=7.02 Hz, 1 H) 3.70 (s, 3 H) 1.91 (s, 2 H) 1.76 - 1.86 (m, 5 H) 1.71 (s, 2 H) 1.66 (d, J=12.82 Hz, 2 H) 1.46 (s, 6 H) 1.36 (d, J=12.51 Hz, 2 H). MS (ESI+) m/z 387 (M+H)+
Example 18
N-adamantan-2-yl-2-r4-chloro-phenoxyV2-methyl-propionamide The title compound was prepared according to the procedure outlined in Example 7C substituting 4-adamantamine hydrochloride for E-4-adamantamine -1-carboxylic acid methyl ester. 1H NMR (400 MHz, DMS0-D6) δ ppm 7.30 - 7.35 (m, 2 H) 7.25 (d, J=7.36 Hz, 1 H) 6.89 - 6.94 (m, 2 H) 3.83 - 3.91 (m, 1 H) 1.82 (d, J=10.74 Hz, 2 H) 1.77 (s, 5 H) 1.64 - 1.73 (m, 5 H) 1.42 - 1.49 (m, 8 H). MS (ESI+) m/z 348 (M+H)+.
Example 19 E-2-(4-Chloro-phenoxyVN-(5-hvdroxy-adamantan-2-ylV2-methyl-propionamide
The title compound was prepared according to the procedure outlined in Example 7C substituting E-4-arninoadamantan-l-ol for E-4-adamantamine -1-carboxylic acid methyl ester. 1H NMR (400 MHz, DMSO-D6) δ ppm 7.30 - 7.35 (m, 2 H) 7.22 (d, J=7.06 Hz, 1 H) 6.88 - 6.94 (m, 2 H) 4.21 - 4.52 (br s, 1 H) 3.75 - 3.80 (m, 1 H) 1.96 (s, 2 H) 1.91 (s, 1 H) 1.64 - 1.71 (m, 2 H) 1.53 - 1.62 (m, 6 H) 1.45 (s, 6 H) 1.27 (d, J=12.58 Hz, 2 H). MS (ESI+) m/z 364 (M+H)+.
Example 20
E-([2-Methyl-2-(4-methylphenoxy)propanoyl]amino>adamantane-l-carboxamide
A solution of the product of Example 12 (24 mg, 0.064 mmol) in DCM (2 mL) was treated with HOBt (9.5 mg, 0.07 mmol) and EDCI (14.7 mg, 0.077 mmol) and stirred at room temperature for 1 hour. Excess of aqueous (30%) ammonia (2 mL) was added and the reaction was stirred for additional 20 hours. The layers were separated and the aqueous layer extracted with DCM (2x2 mL). The combined organic extracts were washed with water (3x2 mL), brine (2 mL), dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the crude compound that was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of 40mL/min. to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.28 (d, J - 7.36 Hz, IH)5 7.08 (d, J= 8.12 Hz, 2H), 6.98-6.99 (bs, IH), 6.80-6.82 (m, 2H), 6.71-6.73 (bs, IH), 3.81-3.86 (m, IH), 2.23 (s, 3H), 1.91-1.93 (m, 2H), 1.77-1.87 (m, 5H), 1.71-1.73 (m, 2H), 1.65-1.70 (m, 2H), 1.41 (s, 6H), 1.37-1.42 (m, 2H). MS (ESI+) m/z 371 (M+H)+.
Example 21 E-4-{r2-f3-Chlorophenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxamide Example 21 A
Example 21 A was prepared according to the procedure outlined in Example ID, substituting 3-chlorophenol for phenol.
Example 2 IB E-A- { [2-(3-ChlorophenoxyV2-methylpropanoyl] amino) adamantane- 1 -carboxamide
The title compound was prepared using the procedure as described in Example IE, substituting the product of Example 21A for the product of Example ID. 1H NMR (500 MHz, DMSOd6) δ ppm 7.35 (d, J= 6.93 Hz, IH), 7.31 (t, J= 8.10 Hz, IH), 7.07 (dd, J= 7.83, 1.91 Hz, IH), 6.97-6.98 (bs, IH), 6.92 (t, J= 2.15 Hz, IH), 6.87 (dd, J= 8.22, 2.29 Hz, IH), 6.70-6.72 (bs, IH), 1.90-1.93 (m, 2H), 1.70-1.71 (m, 2H), 1.49 (s, 6H), 3.80-3.84 (m, IH), 1.76-1.85 (m, 5H), 1.60-1.68 (m, 2H), 1.33-1.37 (m, 2H). MS (ESI+) m/z 391 (M+H)+.
Example 22
E-4-( (2-Methyl-2- r4-(trifluoromethoxy)phenoxy]propanoyl> amino)adamantane- 1 - carboxamide
Example 22A Example 22A was prepared according to the procedure outlined in Example ID, substituting 4-trifluoromethoxyphenol for phenol.
Example 22B
E-4-( {2-Methyl-2-[4-(trifluoromethoxy)phenoxy]propanoyU amino^adamantane- 1 - carboxamide
The title compound was prepared using the procedure as described in Example IE, substituting the product of Example 22A for the product of Example ID. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.41 (t, J= 8.25 Hz, IH), 7.33 (d, J= 6.94 Hz, IH), 7.00 (d, J= 8.15 Hz, IH), 6.90-6.96 (m, 2H), 6.82-6.84 (bs, IH), 6.67-6.69 (bs, IH), 3.79-3.84 (m, IH), 1.87- 1.90 (m, 2H), 1.75-1.86 (m, 5H), 1.69-1.71 (m, 2H), 1.63-1.69 (m, 2H), 1.51 (s, 6H), 1.29- 1.37 (m, 2H). MS (ESI+) m/z 441 (M+H)+. Example 23 E-4- {r2-("3-BromophenoxyV2-methylpropanoyllainino> adamantane- 1 -carboxylic acid
The title compound was prepared according to the procedure outlined in Example ID, substituting 3-bromo-ρhenol for phenol. 1H NMR (500 MHz, DMSOd6) δ ppm 12.05-12.10 (s, IH), 7.38 (d, J= 6.82 Hz, IH), 7.19-7.27 (m, 2H), 7.06 (t, J= 2.06 Hz, IH), 6.91 (ddd, J= 8.09, 2.36, 1.18 Hz, IH), 3.80-3.84 (m, IH), 1.93-1.96 (m, 2H), 1.84-1.85 (m, 4H), 1.77-1.80 (m, IH), 1.74-1.76 (m, 2H), 1.65-1.70 (m, 2H), 1.48 (s, 6H), 1.36-1.40 (m, 2H). MS (ESI+) m/z 437 (M+H)+.
Example 24 4-( { [(YE)- 4- { [2-(4-Chlorophenoxy V 2-methylpropanoyl] amino } - 1 - adamantyDcarbonyll amino>methyl)benzoic acid
To a solution of the product of Example 7C (200 mg, 0.51 mmol) and TBTU (246 mg, 0.77 mmol) in DMF (5 mL) was added N, N-diisopropylethylamine (0.27 mL, 1.53 mmol) followed by 4-aminomethyl-benzoic acid methyl ester hydrochloride (123 mg, 0.61 mmol) and stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo. The residue was taken in ethyl acetate and washed with water and brine respectively, dried (MgSO4) and concentrated in vacuo to get crude methyl ester of the title compound that was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (40mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 12min (15min run time) at a flow rate of 70mL/min. and concentrated. The methyl ester of the title compound was hydrolyzed as described in step B of Example ID. The crude acid product was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (40mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 12min (15min run time) at a flow rate of 70mL/min.to provide the title compound. 1H NMR (400 MHz, DMSOd6) δ ppm 12.77- 12.82 (bs, IH), 8.08 (t, J= 5.96 Hz, IH), 7.88 (d, J= 7.99 Hz, 2H), 7.29-7.36 (m, 5H), 6.91- 6.93 (m, 2H), 4.31 (d, J= 5.86 Hz, 2H), 3.84-3.89 (m, IH), 1.93-1.96 (m, 2H), 1.82-1.91 (m, 5H), 1.77-1.79 (m, 2H), 1.67-1.72 (m, 2H), 1.47 (s, 6H), 1.32-1.45 (m, 2H). MS (ESI+) m/z 525 (M+H)+. Example 25 E-4-{[2-(2,3-Dimethylphenoxy)-2-methylpropanoyllamino>adaniantane-l-carboxylic acid
Example 25A 2-(2,3-Dimethylphenoxy>2-methyl-propionic acid
To an ice cold solution of 2,3-dimethylphenol (136 mg, 1.0 mmol) and 1,1,1- trichloro-2-methyl-2-propanol hydrate (492 mg, 2.75 mmol) in acetone (2 mL) was added powdered sodium hydroxide (393 mg, 9.83 mmol) in three equal portions at 1 hour interval.
After each addition reaction mixture was allowed to come to room temperature. Before last addition of sodium hydroxide, acetone (2 mL) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 48 hours and concentrated in vacuo.
The residue was diluted with water and acidified to pH 1 with aqueous HCl and extracted with diethyl ether (3x5 mL). The organic layers were pooled, dried (Na2SO4) and filtered.
The filtrate was concentrated under reduced pressure to provide the crude that was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (40mm X 100mm,
7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over
12min (15min run time) at a flow rate of 70mL/min. to provide the title compound as a pale yellow solid (158 mg, 76%).
Example 25B
E-4- { [2-(2.3-DimethylphenoxyV2-methylpropanoyl] amino) adamantane- 1 -carboxylic acid To a solution of the product of Example 25A (20.8 mg, 0.1 mmol) and TBTU (48 mg, 0.15 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.052 mL, 0.3 mmol) followed by the product of Example 7B (30 mg, 0.12 mmol) and stirred at room temperature for 20 hours. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of 40mL/min. and hydrolyzed as described in step B of Example ID to provide the title compound. 1H NMR (500 MHz, DMSOd6) δ ppm 12.03- 12.14 (bs, IH), 7.30 (d, J= 7.30 Hz, IH), 6.98 (t, J= 7.79 Hz, IH), 6.84 (d, J= 7.44 Hz, IH), 6.68 (d, J= 8.14 Hz, IH), 3.84-3.88 (m, IH), 2.22 (s, 3H), 2.14 (s, 3H), 1.95-1.97 (m, 2H), 1.83-1.88 (m, 5H), 1.76-1.78 (m, 2H), 1.69-1.73 (m, 2H), 1.41-1.48 (m, 2H), 1.43 (s, 6H). MS (ESI+) m/z 386 (M+H)+.
Example 26 tert-Butyl 4-(2-(r(E)-5-(aminocarbonylV2-adamantyllamino>-lΛ-d.imethyl-2- oxoethoχy)phenylcarbamate
Example 26A
Example 26A was prepared according to the procedure outlined in Example 25A, substituting (4-hydroxy-phenyl)-carbamic acid tert-butyl ester for 2,3-dimethylphenol.
Example 26B
Example 26B was prepared using the procedure as described in Example 25B, substituting the product of Example 26A for the product of Example 25 A.
Example 26C tert-Butyl 4-(2-{r(E)-5-(aminocarbonylV2-adamantyllamino>-U-dimethyl-2- oxoethoxy)phenylcarbamate
The title compound was prepared using the procedure as described in Example IE, substituting the product of Example 26B for the product of Example ID. 1H NMR (400 MHz, DMSOd6) δ ppm 9.18-9.20 (bs, IH), 7.34 (d, J= 8.50 Hz, 2H), 7.28 (d, J= 7.37 Hz, IH), 6.96-6.98 (bs, IH), 6.84 (d, J= 8.77 Hz, 2H), 6.68-6.70 (bs, IH), 3.81-3.87 (m, IH), 1.92-1.95 (m, 2H)5 1.80-1.89 (m, 5H), 1.68-1.75 (m, 4H), 1.46 (s, 9H)5 1.39-1.46 (m, 2H), 1.39 (s, 6H). MS (ESI+) m/z 472 (M+H)+.
Example 27
E-N-[4-(AminocarbonvDbenzyll-4-{[2-(4-chlorophenoxyV2- methylpropano yl] amino) adamantane- 1 -carboxamide '
The title compound was prepared according to the procedure outlined in Example IE substituting the product of Example 24 for the product of Example ID. 1H NMR (400 MHz, DMSOd6) δ ppm 8.03-8.08 (m, IH), 7.86-7.88 (bs, IH), 7.80 (d, J= 8.09 Hz, 2H), 7.32-7.35 (m, 2H), 7.26-7.32 (m, 2H), 7.24-7.27 (m, 2H), 6.91-6.93 (m, 2H), 4.29 (d, J= 5.87 Hz, 2H), 3.83-3.89 (m, IH), 1.82-1.96 (m, 7H), 1.77-1.79 (m, 2H), 1.66-1.72 (m, 2H), 1.46 (s, 6H), 1.37-1.42 (m, 2H). MS (ESI+) m/z 524 (M+H)+.
Example 28
E-N-[4-(AminocarbonvDmethyll-4-{[2-r4-chloroplienoxyV2- methylpropano yll amino ) adamantane- 1 -carboxamide
Example 28A
Example 28A was prepared according to the procedure outlined in Example 24, substituting glycine methyl ester hydrochloride for 4-aminomethyl-benzoic acid methyl ester hydrochloride.
Example 28B i?-N-[4-(AminocarbonvDmethyl1 -4- { [2-f 4-chlorophenoxy)-2- methylpropano yl] amino} adamantane- 1 -carboxamide
The title compound was prepared using the procedure as described in Example IE, substituting the product of Example 28 A for the product of Example ID. 1H NMR (400 MHz, DMSOd6) δ ppm 7.49-7.54 (m, IH), 7.32-7.35 (m, 2H), 7.31 (d, J= 7.21 Hz, IH), 7.08-7.11 (bs, IH), 6.93-6.97 (m, IH), 6.91-6.93 (m, 2H), 3.82-3.87 (m, IH), 3.58 (d, J= 5.68 Hz, 2H), 1.92-1.98 (m, 2H), 1.80-1.90 (m, 5H), 1.74-1.76 (m, 2H), 1.65-1.71 (m, 2H), 1.46 (s, 6H), 1.36-1.41 (m, 2H). MS (ESI+) m/z 448 (M+H)+.
Example 29
3-((J((E)-4-l[2-('4-Chlorophenoxy)-2-methylpropanoyllamino>-l- adamantvDcarbonyljaminolmethyDbenzoic acid
The title compound was prepared according to the procedure outlined in Example 24, substituting 3-aminoniethyl-benzoic acid methyl ester hydrochloride for 4-aminomethyl- benzoic acid methyl ester hydrochloride. 1H NMR (400 MHz, DMSOd6) δ ppm 12.81-12.91 (m, IH), 8.06-8.12 (m, IH), 7.77-7.82 (m, 2H), 7.40-7.44 (m, 2H), 7.31-7.35 (m, 2H), 7.30- 7.32 (m, IH), 6.91-6.93 (m, 2H), 4.30 (d, J= 5.89 Hz, 2H), 3.83-3.88 (m, IH), 1.93-1.96 (m, 2H), 1.82-1.90 (m, 5H), 1.77-1.79 (m, 2H), 1.67-1.72 (m, 2H), 1.46 (s, 6H), 1.37-1.42 (m, 2H). MS (ESI+) m/z 525 (M+H)+. Example 30 E-A-( (2-Ff 5-Bromopyridin-2-yl)oxy1-2-methylpropanoyl} amino)adamantane- 1 -carboxamide
Example 3OA
2-(5-Bromo-pyridin-2-yloxyV2-methyl-propionic acid Step A
To a stirred and cooled (O0C) solution of 2-hydroxy-2-methyl-propionic acid methyl ester (2.6 mL, 22.70 mmol) and 5-bromo-2-fluoro-pyridine (3.32 g, 18.92 mmol) in THF (26 mL) and DMPU (13 mL) was added portionwise NaH (Ig, 60% in oil, 24.59 mmol). After the addition, the resulting mixture was warmed to room temperature and stirred overnight. Saturated NH4Cl was then added to quench the reaction and Et2O was used to partition the mixture. The organic phase was washed with water, brine, dried over MgSO4, and filtered. After concentration, the residue was purified over silica gel using 20% EtOAc / hexane and concentrated to give a clear oil. Step B
The product of Step A (1.56 g, 5.71 mmol) was dissolved in THF (30 mL) and KOTMS (1.1 g, 8.57 mmol) was added in one portion. The resulting solution was stirred at room temperature overnight. Et2O (30 mL) and water (40 mL) were added to the reaction to partition the mixture. The phases were separated, and the aqueous phase was acidified using 10% NaHSO4 solution and extracted with EtOAc. The combined organic phases were dried over MgSO4, filtered and concentrated to give the title compound as a white solid.
Example 3OB E-4-({2-[('5-Bromor)yridin-2-yl)oxyl-2-methylpropanoyl>amino^adamantane-l-carboxamide Step A
HATU (2.46 g, 6.48 mmol) was added in one portion to a solution of the product of Step B of Example 3OA (1.40 g, 5.40 mmol), the product of Example 7B (1.45 g, 5.95 mmol), and DIPEA (2.82 mL, 16.2 mmol) in dry CH2Cl2 (20 mL). The resulting solution was allowed to stir at room temperature overnight before it was diluted with CH2Cl2 and washed with aqueous NaHSO4 solution, 1 M NaOH, dried (Na2SO4) and evaporated. The residue was purified over silica gel using 30% EtOAc / hexanes and concentrated to give an oil. Step B
To the product of Step A (2.27 g, 5.04 mmol) in THF (15 mL) was added KOTMS (1.42 g, 11.08 mmol) and the resulting solution was stirred at room temperature overnight before it was diluted with Et2O and water. The phases were separated and the aqueous phase was acidified with NaHSO4 solution and extracted with EtOAc. The combined organic phases were dried (MgSO4) and evaporated to give a white solid. Step C
EDCI (1.40 g, 7.25 mmol) was added to a solution of the product of Step B (2.17 g, 4.84 mmol), HOBt (1.17 g, 8.71 mmol), DIPEA (2.5 mL, 14.4 mmol) in dry CH2Cl2 (20 mL). The resulting solution was allowed to stir at room temperature for 1 hr before NH3 solution was added (12 mL, 2M in iPrOH). The mixture was stirred for 2 hours at 250C, diluted with CH2Cl2 and washed with NaHSO4 solution, IM NaOH, brine, dried (Na2SO4) and evaporated. The residue was purified over silica gel using 5% MeOH / CH2Cl2 to give the title compound as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 8.11 (d, J= 2.52 Hz, IH), 7.82 (dd, J= 8.74, 2.60 Hz, IH), 6.84 (d, J= 8.74 Hz, IH), 3.89-3.92 (m, IH), 1.91-1.99 (m, 6H), 1.83 (s, 3H), 1.66 (s, 6H), 1.41-1.62 (m, 4H). MS (ESI+) m/z 436 (M+H)+.
Example 31
E-A- { [2-(2-C vanophenoxy)-2-methylpropanoyl] amino) adamantane- 1 -carboxamide
Example 31A
Example 31 A was prepared according to the procedure outlined in Example 25 A, substituting 2-hydroxy-benzonitrile for 2,3-dimethylphenol.
Example 3 IB
Example 3 IB was prepared using the procedure as described in Example 25B, substituting the product of Example 31A for the product of Example 25A.
Example 31C E-A- { [2-(2-C vanophenoxyV2-methylpropano yl] amino! adamantane- 1 -carboxamide
The title compound was prepared using the procedure as described in Example IE, substituting the product of Example 31B for the product of Example ID. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.78 (dd, J= 7.68, 1.75 Hz, IH), 7.62 (ddd, J= 8.54, 7.48, 1.68 Hz, IH), 7.49 (d, J= 6.94 Hz, IH), 7.17 (td, J= 7.58, 0.87 Hz, IH), 7.08 (d, J= 8.53 Hz, IH), 6.98-6.99 (bs, IH), 6.71-6.72 (bs, IH), 3.83-3.87 (m, IH), 1.94-1.96 (m, 2H), 1.75-1.88 (m, 7H), 1.71-1.73 (m, 2H), 1.60 (s, 6H), 1.35-1.39 (m, 2H). MS (ESI+) m/z 382 (M+H)+.
Example 32 E-4-{[2-(4-Hvdroxyphenoxy)-2-methylpropanoyl] amino) adamantane-1-carboxamide
Example 32 A Example 32A was prepared according to the procedure outlined in Example 25 A, substituting 4-benzyloxy-phenol for 2,3-dimethylphenol.
Example 32B
Example 32B was prepared according to the procedure outlined in Example 25B, substituting the product of Example 32A for the product of Example 25 A.
Example 32C
Example 32C was prepared according to the procedure outlined in Example IE, substituting the product of Example 32B for the product of Example ID.
Example 32D E-4-{[2-(4-Hvdroxyphenoxy)-2-methylpropanoyl]amino|adamantane-l-carboxamide
The product of Example 32C (62 mg, 0.13 mmol) was debenzylated using 20% Pd(OH)2/C (63 mg) and methanol (2mL) at 60 psi at room temperature for 20 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide the crude product that was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of 40mL/min. to provide title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (s, IH), 7.28 (d, J= 7.49 Hz, IH), 6.96-6.99 (bs, IH), 6.77-6.79 (m, 2H), 6.69-6.71 (bs, IH), 6.63- 6.69 (m, 2H), 3.81-3.87 (m, IH), 1.93-1.95 (m, 2H), 1.78-1.89 (m, 5H), 1.69-1.76 (m, 4H), 1.42-1.47 (m, 2H), 1.35 (s, 6H). MS (ESI+) m/z 373 (M+H)+. Example 33 ((E)-4-{[2-(4-ChloroplienoxyV2-methylpropanoyl"|ammo>-l-adamantyl')acetic acid
Example 33 A
2-(4-chlorophenoxyVN-[(E)-5-(hydroxymetliylV2-adamantyl]-2-methylpropanamide
To a cold (-300C) solution of the methyl ester of Example 7C (870 mg, 2.15 mmol) in THF (3.0 niL) was added IN LAH in THF solution (3.22 ml, 3.22 mmol) slowly under N2 flow. The reaction mixture was stirred from -30°C to 00C for 3 hours. It was quenched with water carefully, acidified with IN HCl and extracted with DCM 3 times. The combined organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure and the residue purified by flash chromatography with 30% ethyl acetate / 70% hexane to provide the title compound (690 mg, 85%). 1H NMR (300 MHz, CDCl3) δ ppm 9.32 - 9.39 (m, 1 H), 7.17 - 7.29 (m, 2 H), 7.00 (d, 1 H), 6.81 - 6.91 (m, 2 H), 3.99 - 4.12 (m, 1 H), 1.44 - 2.15 (m, 21 H). MS (ESI+) m/z 378 (M+H)+.
Example 33B E-4-[2-(4-ChlorophenoxyV2-methyl-propionylamino]-adamantane-l-carbaldehyde
To a solution of the product of Example 33A (990 mg, 2.63 mmol) in DCE (8.0 mL) were added NMO (461 mg, 3.94 mmol), TPAP (46 mg, 0.13 mmol) and molecular sieves at room temperature under N2 flow. The reaction mixture was stirred overnight at room temperature. It was filtered through Celite and washed with DCM 3 times. The combined filtrate was concentrated under reduced pressure and purified by flash chromatography with 30% ethyl acetate / 70% hexane to provide the title compound (740 mg, 75%). 1H NMR (300 MHz, CDCl3) δ ppm 9.36 (m, 1 H), 7.20 - 7.26 (m, 2 H), 6.95 - 7.05 (m, 1 H), 6.82 - 6.91 (m, 2 H), 4.00 - 4.10 (m, 1 H), 1.48 - 2.13 (m, 19 H). MS (ESI+) m/z 376 (M+H)+.
Example 33C
E-{4-[2-(4-ChlorophenoxyV2-methyl-propionylaminol-adamantan-l-yll-acetonitrile To a cold (O0C) solution of the product of Example 33B (375 mg, 1 mmol) in DME
(5.0 mL) / EtOH (0.15 ml) was added TosMIC (254 mg, 1.3 mmol) and t-BuOK (281 mg, 2.5 mmol) under N2 flow. The reaction mixture was stirred at room temperature for 2 hrs, then heated to 35-4O0C for 30 minutes. It was filtered through Al2O3 plug after it was cool down to room temperature and washed with DME (3 X). The combined filtrate was concentrated under reduced pressure and purified by flash chromatography with 30% ethyl acetate/ 70% hexane to provide the title compound (200 mg, 52%). 1H NMR (400 MHz, CDCl3) δ ppm 7.19 - 7.29 (m, 2 H), 6.91 - 7.01 (m, 1 H), 6.81 - 6.90 (m, 2 H), 3.96 - 4.05 (m, 1 H), 2.14 (s, 2 H), 1.94 - 2.08 (m, 3 H), 1.47 - 1.75 (m, 15 H). MS (ESI+) m/z 387 (M+H)+.
Example 33D r(E)-4-([2-(4-Chlorophenoxy)-2-methylpropanovnammo|-l-adamantyl')acetic acid To a solution of the product of Example 33C (40 mg, 0.1 mmol) in ethylene glycol
(0.5 ml) was added 25% KOH solution (0.2 ml). The reaction mixture was heated to 15O0C overnight and concentrated. The residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of 40mL/min. to provide the title compound (19 mg, 45%). 1H NMR (400 MHz, CDCl3) δ ppm 7.19 - 7.25 (m, 2 H), 6.96 - 7.02 (m, 1 H), 6.82 - 6.90 (m, 2 H), 3.98 - 4.07 (m, 1 H), 2.11 - 2.18 (m, 2 H), 1.88 - 2.03 (m, 3 H), 1.47 - 1.85 (m, 16 H). MS (ESI+) m/z 406 (M+H)+.
Example 34 N-[rE)-5-(2-Amino-2-oxoethyl)-2-adamantyl1-2-(4-chlorophenoxy)-2-methylpropanamide
To a solution of the product of Example 33C (22 mg, 0.057 mmol) in MeOH (0.15 ml) / DMSO (0.005 ml) were added 30% H2O2 (0.011 ml) and 0.2 M NaOH (0.006 ml). The reaction mixture was heated to 5O0C overnight and concentrated. The residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of 40mL/min. to provide the title compound (13 mg, 56%). 1H NMR (500 MHz, CDCl3) δ ppm 7.21 - 7.26 (m, 2 H), 6.94 - 7.04 (m, 1 H), 6.84 - 6.91 (m, 2 H), 5.62 - 5.72 (m, 1 H), 5.35 - 5.43 (m, 1 H), 3.97 - 4.06 (m, 1 H), 1.89 - 2.05 (m, 5 H), 1.48 - 1.80 (m, 18 H). MS (ESI+) m/z 405 (M+H)+.
Example 35 2-r4-ChlorophenoxyV2-methyl-N-r(E)-5-C2H-tetraazol-5-vhnethylV2- adamantvUpropanamide
To a solution of the product of Example 33C (65 mg, 0.168 mmol) in water (0.2 ml) / isopropanol (0.1 ml) were added NaN3 (22 mg, 0.337 mmol) and ZnBr2 (19 mg, 0.084 mmol). The reaction mixture was heated to 15O0C in a sealed tube for two days and concentrated. The residue was purified by reverse phase preparative HPLC on a Waters
Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of 40mL/min. to provide the title compound (43 mg, 45%). 1H NMR (400 MHz, CD3OD) δ ppm 7.34 - 7.43 (m, 1 H)5 7.23 - 7.31 (m, 2 H), 6.89 - 6.96 (m, 2 H), 3.84 - 3.92 (m, 1 H), 2.75 (s, 2 H), 1.86 - 2.02 (m, 3 H), 1.43 - 1.74 (m, 16 H). MS (ESI+) m/z 430 (M+H)+.
Example 36 N-{(E)-5-["(Αminosulfonyl)methyl1-2-adamantyl}-2-r4-chlorophenoxy)-2- methylpropanamide
Example 36A N-((.£D-5-[(Thioacetyl)methyl1-2-adamantvU-2-('4-chlorophenoxy)-2-methylpropanamide
To a 0 0C solution of the product of Example 33A (0.71 g, 1.88 mmol) in CH2Cl2 (5.0 mL) and pyridine (0.46 mL, 5.64 mmol) was added trifluoromethanesulfonic anhydride (0.35 mL, 2.07 mmol). The reaction mixture was stirred under an atmosphere of N2 for 30 min at O0C. The crude products were diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was dissolved in DMF (5.0 mL), treated with potassium thioacetate (0.43 g, 3.76 mmol), and heated to 7O0C overnight. The crude reaction mixture was diluted with EtOAc, washed with water (3x) and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography employing a solvent gradient (hexane→60:40 hexane:EtOAc) to yield the title compound(0.74 g, 90%) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.23 (d, J= 8.82 Hz, 2 H), 6.95 (m, 1 H), 6.86 (d, J=8.82 Hz, 2 H), 3.98 (m, 1 H), 2.76 (s, 2 H), 2.35 (s, 3 H), 1.89 - 1.97 (m, 3 H) 1.45-1.68 (m, 10 H), 1.50 (s, 6H). MS (ESI+) m/z 436 (M+H)+.
Example 36B N-{(E)-5-r(Sulfonic acid)methyl1-2-adamantyl}-2-(4-chlorophenoxyV2-methylpropananiide To a solution of the product of Example 36A (0.74 g, 1.70 mmol) and NaOAc (0.1392 g, 1.70 mmol) in acetic acid (10 niL) was added 30% hydrogen peroxide in water (1.6 niL, 15.3 mmol). The reaction solution was stirred at room temperature overnight and excess peroxide quenched by adding dimethylsulfϊde (1.9 mL, 25.5 mmol) and stirring for 2 h. The reaction solution was concentrated under reduced pressure to provide the crude product as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.22 (d, J= 8.85 Hz, 2 H), 7.07 (d, J= 7.94 Hz, 1 H), 6.86 (d, J=8.85 Hz, 2 H), 3.95 (m, 1 H), 2.80 (s, 2 H), 1.51 - 2.17 (m, 13 H) 1.46 (s, 6H). MS (ESI+) m/z 442 (M+H)+.
Example 36C «
N-l(E)-5-[(Aminosulfonyl)methyll-2-adamantyl}-2-(4-chlorophenoxyV2- methylpropanamide
To a solution of the product of Example 36B (55.8 mg, 0.126 mmol) in DCM (1.2 mL) and DMF (1 drop) was added triphosgene (27.4 mg, 0.0922 mmol) and triethylamine (0.018 mL, 0.126 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours and ammonia (0.5 M in dioxane, 2.5 mL, 1.26 mmol) was added. After stirring for 2 h at room temperature the reaction was quenched with water and extracted with EtOAc. The organic layer was then rinsed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC using acetonitrile:10niM NH4OAc on YMC Guardpak column to provide the title compound (20 mg, 36%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.24 (d, J= 8.9 Hz, 2 H), 6.98 (d, J= 8.28 Hz, 1 H), 6.86 (d, J=8.9 Hz, 2 H), 4.79 (s, 2H), 4.04 (m, 1 H), 3.04 (s, 2H), 1.87-2.04 (m, 8 H), 1.54-1.66 (m, 5 H), 1.50 (s, 6H). MS (ESI+) m/z 441 (M+H)+.
Example 37
N-(('E)-5-f(Z')-Amino(hvdroxyimino>)methyl]-2-adamantvU-2-(4-chlorophenoxyV2- methylpropanamide
Example 37A
("5-Carbamoyl-adamantan-2-ylVcarbamic acid benzyl ester Step A CbzCl (3.48 niL, 24.72 mmol) was added dropwise to a stirred and cooled (O0C) solution of the product of Example 7B (5.05 g, 20.60 mmol) and DIPEA (7.9 mL, 45.32 mmol) in dry CH2Cl2 (100 mL). After the addition, the solution was allowed to warm to room temperature and stirred for another 2 hrs. Saturated NaHCO3 solution was added to quench the reaction and the phases were separated. The organic phase was washed with NaHSO4 solution, NaHCO3 solution, dried (Na2SO4), filtered, and concentrated. The residue was purified over silica gel using 20% EtOAc in hexanes and concentrated. Step B
The product of step A (6.49 g, 18.91 mmol) was dissolved in dry THF (90 mL) and KOTMS (4.85 g, 37.82 mmol) was added at room temperature. The resulting solution was stirred overnight before water (100 mL) and Et2O (100 mL) were added and the phases were separated. The aqueous phase was acidified using solid NaHSO4 until pH 1 was reached. The aqueous phase was then extracted using EtOAc. The combined organic extract was dried (MgSO4), filtered, and concentrated. Step C
The product of Step B (18.91 mmol) was dissolved in dry CH2Cl2 (60 mL) and DIPEA (10 mL, 56.7 mmol), HOBt (5.1 g, 37.82 mmol), and EDCI (5.4 g, 28.36 mmol) were added to the solution. The resulting mixture was stirred for 1 h before NH3 (30 mL, 2 M in iPrOH, 56.7 mmol) was added. After 1 h of stirring at 25 0C, the solution was diluted with CH2Cl2 (200 mL) and washed with NaHSO4 solution, 1 M NaOH, water, dried (Na2SO4) and filtered. The residue was purified over silica gel using 5% MeOH in CH2Cl2 to provide the title compound as a solid.
Example 37B E-4- Amino-adamantane- l-carbonitrile
Step A
The product of Step C of Example 37 A, 18.91 mmol) was dissolved in dry CH2Cl2 (60 mL) and Et3N (10.5 mL, 75.64 mmol). TFAA (7.9 mL, 56.73 mmol) was added dropwise to the solution at 00C. After the addition, the solution was allowed to warm to room temperature and stirred for 3 hours before MeOH was added to quench the reaction. The solution was washed with TSIaHSO4 solution, NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The residue was purified over silica gel using 30% EtOAc in hexanes and concentrated to yield an oil. Step B
Pd(OH)2 / C (0.9 g) was added to a solution of the product of Step A (3.22 g, 10.38 mrnol). The solution was stirred at room temperature under H2 (balloon) until starting material was consumed. The mixture was filtered through a pad of Celite and concentrated in vacuo to provide the title compound as a solid.
Example 37C 2-(4-Chloro-phenoxy)-N-[('E)-5-(lSf-hvdroxycarbamimidoyl)-adamantan-2-yll-2-methyl- propionamide
Step A
HATU (0.64 g, 1.67 mmol) was added in one portion to a stirred solution of 2-(4- chloro-phenoxy)-2-methyl-propionic acid (0.3 g, 1.50 mmol) and the product of Step B of Example 37B (0.27 g, 1.53 mmol), and DIPEA (0.73 mL, 4!2 mmol) in dry DMF (7 mL). The reaction was allowed to stir for 5 hours before it was diluted with CH2Cl2 and washed with NaHSO4 solution, IM NaOH, brine, and dried (Na2SO4), and evaporated. The residue was purified over silica gel using 20% EtOAc / hexanes and concentrated to yield a white solid. Step B To the product of Step A (87 mg, 0.209 mmol) was added NH3OHCl (87 mg, 1.25 mmol), DIPEA (0.29 mL, 1.67 mmol) and dry DMSO (1 mL). The resulting solution was heated at 800C for 8 hrs. The solvent was evaporated and the residue was purified on HPLC using CH3CN / water 1% TFA as eluent to provide the title compound as an oil. 1H NMR (300 MHz, CD3OD) δ ppm 7.49-7.54 (m, IH), 7.26-7.30 (m, 2H)5 6.92-6.96 (m, 2H), 3.97- 4.03 (m, IH), 2.10-2.15 (m, 2H), 1.98-2.08 (m, 5H), 1.92-1.94 (m, 2H), 1.76-1.83 (m, 2H), 1.57-1.64 (m, 2H), 1.53 (s, 6H). MS (ESI+) m/z 406.1(M+H)+.
Example 38
E-N-[4-(Aminosulfonyl)benzyll-4-(["2-(4-chlorophenoxy)-2- methylpropanoyl]ammo)adamantane-l-carboxamide
The title compound was prepared according to the procedure outlined in Example 24, substituting 4-aminomethyl-benzenesulfonamide hydrochloride for 4-aminomethyl-benzoic acid methyl ester hydrochloride. 1HNMR (500 MHz, DMSO-d6) δ ppm 8.10-8.15 (m, IH), 7.75 (d, J= 8.08 Hz, 2H)3 7.37 (d, J= 8.03 Hz5 2H), 7.31-7.35 (m,.3H), 7.29-7.29 (bs, 2H), 6.91-6.93 (m, 2H), 4.30 (d, J= 5.87 Hz, 2H), 3.84-3.88 (m, IH), 1.93-1.95 (m, 2H), 1.82-
1.92 (m, 5H), 1.76-1.78 (m, 2H), 1.67-1.71 (m, 2H), 1.46 (s, 6H), 1.37-1.41 (m, 2H). MS (ESI+) m/z 560 (M+H)+.
Example 39
E-4- { [2-(4-ChlorophenoxyV2-methylpropanoyl] amino) -N-(4- { [(methylsulfonyDaminoJcarbonvUbenzvDadamantane- 1 -carboxamide To a solution of the product of Example 24 (26 mg, 0.05 mmol) in DMF (1 mL) were added DMAP (7 mg, 0.055 mmol), EDCI (12 mg, 0.06 mmol) and methylsulfonamide (7 mg, 0.075 mmol). The reaction mixture was stirred at room temperature for 72 hours, concentrated in vacuo, and the residue was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of
40mL/min. to provide the title compound. 1H NMR (400 MHz, DMSOd6) δ ppm 12.01- 12.05 (bs, IH), 8.11 (t, J= 6.06 Hz, IH), 7.87 (d, J= 8.19 Hz, 2H), 7.30-7.37 (m, 5H), 6.91-
6.93 (m, 2H), 4.31 (d, J= 5.89 Hz, 2H), 3.83-3.87 (m, IH), 3.36 (s, 3H), 1.82-1.96 (m, 7H), 1.77-1.79 (m, 2H), 1.67-1.72 (m, 2H), 1.47 (s, 6H), 1.37-1.42 (m, 2H). MS (ESI+) m/z 602 (M+H)+.
Example 40 E-4-( {2-[(4-Chlorophenyl)thio1-2-methylρropanoyl| amino)adarnantane-l -carboxylic acid
Example 4OA
Example 4OA was prepared according to the procedure outlined in Example 25A, substituting 4-chloro-benzenethiol for 2,3-dimethylphenol.
Example 4OB E-4-((2-r(4-Chlorophenyl)thio1-2-methylproρanoyl>amino')adamantane-l-carboxylic acid
The title compound was prepared according to the procedure outlined in Example 25B, substituting the product of Example 4OA for the product of Example 25A. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.42-7.45 (m, 2H), 7.36-7.39 (m, 2H), 7.11-7.21 (m, IH), 3.72- 3.78 (m, IH), 1.91-1.94 (m, 2H), 1.79-1.92 (m, 6H), 1.75-1.80 (m, 3H), 1.44 (s, 8H). MS (ESI+) m/z 408 (M+H)+.
Example 41
£-4-({2-[(4-Methoxyphenyl)thio1-2-niethylpropanovUamino)adamantane-l-carboxamide amide
Example 41A E-4-(2-Bromo-2-methyl-propionylammoVadamantane- 1 -carboxylic acid
A solution of the product of Example IB (0.78 g, 2.48 mmol) in 99% formic acid (2.5 mL) was added dropwise with vigorous gas evolution over 10 minutes to a rapidly stirred 30% oleum solution (7.5 mL) heated to 6O0C (W. J. Ie Noble, S. Srivastava, C. K. Cheung, J. Org. Chem. 48: 1099-1101, 1983). Upon completion of addition, more 99% formic acid (2.5 mL) was slowly added over the next 10 minutes. The mixture was stirred for another 60 minutes at 6O0C and then slowly poured into vigorously stirred iced water (30.0 mL) cooled to O0C. The mixture was allowed to slowly warm to 23°C, filtered and washed with water to neutral pH (100 mL). The precipitate was dried in a vacuum oven overnight to provide the title compound.
Example 41B
■Z?-4-(2-Bromo-2-methyl-proρionylamino)-adamantane- 1 -carboxylic acid amide A solution of the product of Example 41 A (250 mg, 0.670 mmol) in DCM (30 mL) was treated with HOBt (109 mg, 0.80 mmol) and EDCI (154 mg, 0.80 mmol) and stirred at room temperature for 3 hour. Excess of aqueous (30%) ammonia (20 mL) was added and the reaction was stirred for additional 20 hours. The layers were separated and the aqueous layer extracted twice more with methylene chloride (2x40 mL). The combined organic extracts were washed with water (3x20 mL) and brine (2OmL); dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide the crude title compound that was purified by normal phase column chromatography (silica gel, 5% methanol in DCM) to afford the title compound. MS (ESI+) m/z 343 (M+H)+. Example 41 C E-4-r2-(4-Methoxy-phenylsulfanyl)-2-methyl-propionylamino1-adamantane-l-carboxylic acid amide
A solution of 4-methoxy-benzenethiol (44 mg, 0.31 mmol) and sodium hydride (60%, 15.0 mg, 0.37 mmol) in toluene (4 mL) was stirred at room temperature for 1 hour. The product of Example 41B (106.0 mg, 0.31 mmol) was added to the solution and the resulting mixture was stirred at 1000C for 24 hours. The reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to provide crude product that was purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of 40mL/min. to afford the title compound. 1H NMR (500 MHz, DMSOd6) δ ppm 7.33-7.35 (m, 2H), 7.11 (d, J= 7.18 Hz, IH), 6.99-7.01 (s, IH), 6.93-6.95 (m, 2H), 6.72-6.74 (s, IH), 3.75-3.79 (m, IH), 3.77 (s, 3H), 1.79-1.95 (m, 9H), 1.75-1.77 (m, 2H), 1.44-1.48 (m, 2H), 1.39 (s, 6H). MS (ESI+) m/z 403 (M+H)+.
Example 42 E-4-r{2-rr4-Methoxyphenyπsulfinyl1-2-methylpropanoyl>amino)adamantane-l-carboxamide
A solution of the product of Example 41C (53 mg, 0.087 mmol) in methanol (5 mL) was treated with OXONE (80 mg, 0.130 mmol) and stirred at room temperature for 7 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to provide crude title compound that was subsequently purified by reverse phase preparative HPLC on YMC Guardpak column using a gradient of 0% to 70% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of 40mL/min. to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.49-7.52 (m, 2H), 7.32 (d, J= 6.93 Hz, IH), 7.09- 7.12 (m, 2H), 6.96-6.99 (s, IH), 6.68-6.71 (s, IH), 3.82 (s, 3H), 3.75-3.81 (m, IH), 1.89-1.92 (m, 3H), 1.73-1.86 (m, 8H), 1.42-1.51 (m, 2H), 1.34 (s, 3H), 1.25 (s, 3H). MS (ESI+) m/z 419 (M+H)+.
Example 43 E-4-r{2-rr4-Methoxyphenyl')sulfonyl]-2-methylpropanovUamino')adamantane-l-carboxamide
A solution of the product of Example 41C (53 mg, 0.087 mmol) in methanol (5 mL) was treated with OXONE (80 mg, 0.130 mmol) and stirred at room temperature for 24 hour. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to provide crude title compound that was subsequently purified by reverse phase preparative HPLC on a Waters Symmetry C8 column (25mm X 100mm, 7um particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 8min (lOmin run time) at a flow rate of 40mL/min. to afford the title compound. 1H NMR (400 MHz, DMSOd6) δ ppm 7.72 (d, J= 8.65 Hz, 2H), 7.17-7.20 (m, 3H), 6.97-6.99 (s, IH), 6.70-6.72 (s, IH), 3.88 (s, 3H), 3.77-3.83 (m, IH), 1.94-1.97 (m, 3H), 1.82-1.89 (m, 6H), 1.76-1.78 (m, 2H), 1.49-1.54 (m, 2H), 1.45 (s, 6H). MS (ESI+) m/z 435 (M+H)+.
Example 44
E-4-({2-|~4-Chloro-2-φyrrolidm-l-ylsulfonvnτ)henoxyl-2- methylpropano yl) amino)adamantane- 1 -carboxamide
Example 44A 2-Hydroxy-5-chlorobenzene sulfonyl chloride
4-Chlorophenol (4 g, 31.25 mmol) was added in portions to chlorosulfonic acid (10.3 mL, 156 mmol) while cooling in an ice bath. The resulting solution was stirred at 25°C for 20 hrs. This was then added drop-wise to ice and water resulting in an emulsion. This was extracted with CHCl3, dried (Na2SO4) and concentrated in vacuo. Heptane was added and evaporated and replaced with cyclohexane. The resulting mixture was filtered and concentrated to give the title compound as an oil (2.16 g).
Example 44B
2-Hvdroxy-5-chlorobenzene sulfonyl pyrrolidine To a solution of the product of Example 44A (2.16 g, 9.51 mmol) in CHCl3 (8 mL) was added, with ice cooling, pyrrolidine (4.05 g, 57.04 mmol). The mixture was stirred at 250C for 2 hrs, then concentrated in vacuo. The residue was dissolved in toluene, washed with HCl and water, dried (Na2SO4) and concentrated. The resulting oil was crystallized from hexane and chromatographed (CH2Cl2) to yield the title compound (1.92 g), m.p.101- 102°C.
Example 44C 2- [4-Chloro-2-(p yrrolidine- 1 -sulfonylVphenoxy] -2-methyl-propionic acid The product of Example 44B (1.0 g, 3.82 mmol) and l,l,l-trichloro-2-methyl-2- propanol hydrate (1.832 g, 10.32 mmol) were dissolved in acetone (8.5 mL). Powdered NaOH (0.47 g. 11.75 mmol) was added with cooling. The resulting mixture was stirred for 1.5 hr at 25°C. A second batch of powdered NaOH (0.47 g) was added and stirred for another 1.5 hrs. The last batch of powdered NaOH (0.47 g) was then added along with acetone (2.5 mL). The resulting mixture was stirred for 15 hrs at 25°C. Acetone was added and the solution was filtered. The resulting solution was concentrated. Water (3 mL) was added and concentrated HCl was added to acidify the mixture, which was extracted with toluene, dried and concentrated. The residue was chromatographed on silica gel. Eluting with CH2Cl2 gave 380 mg recovered starting material. Changing to 5% MeOH in ethyl acetate gave the title compound (357 mg, 27% yield).
Example 44D E-4-("(2-r4-Chloro-2-rpyrrolidin-l-ylsulfonvDphenoxyl-2- methylpropanovU amino)adamantane- 1 -carboxamide
The product of Example 7B (75 mg, 0.305 mmol), the product of Example 44C (116 mg, 0.335 mmol), and TBTU (108 mg, 0.336 mmol) were suspended in dimethylacetamide (0.5 mL). Diisopropylethylamine (135 mg, 1.05 mmol) was added and the resulting solution stirred at 25°C for 15 hrs. Toluene was added, and concentrated. More toluene was added, and washed with dil H3PO4, H2O, and then KHCO3. The organic phase was dried (Na2SO4), and filtered. The solvents were removed in vacuo and the residue crystallized from ether and heptane to yield the title compound (133 mg), m.p. 152-1540C.
Example 44E
E-4-(2-[4-Chloro-2-(pyrrolidme-l-sulfonylVphenoxy1-2-methyl-propionylamino}- adamantane-1-carboxylic acid
A solution of the product of Example 44D (125 mg, 0.231 mmol) in MeOH (0.75 mL) was treated with NaOH (100 mg) in water (0.5 mL). The mixture was heated until all was soluble and stirred at 6O0C for 1 hour. The solvent was removed in vacuo and the residue acidified with HCl, extracted with CHCl3, dried (Na2SO4), filtered, and concentrated. The residue was crystallized from ether to yield the title compound (92 mg, 77% yield), m.p. 226- 228°C.
Example 44F
E-4-d2-r4-Chloro-2-(pyrrolidin-l-ylsulfonyl)phenoxyl-2- methylpropano yl) amino)adarnantane- 1 -carboxamide
The product of Example 44E (76 mg, 0.145 mmol), TBTU (52 mg, 0.162 mmol), and diisopropylethylamine (40 mg, 0.31 mmol) were dissolved in N5N-dimethylacetamide (0.3 niL). After 25 min. at 25°C, a solution of 10% ammonia in THF was added. A solid formed and the mixture was stirred for3 hrs at 25°C. Toluene was added and the mixture concentrated in vacuo. The residue was dissolved in CHCl3 and washed with dil H3PO4, H2O, and KHCO3; dried (Na2SO4), filtered and concentrated in vacuo. The residue was crystallized from ether to yield the title compound (64 mg, m.p. 249-252°C). 1H NMR (400MHz, CDCl3) δ ppm 7.85 (d, J= 2 Hz, IH), 7.37 (dd, J= 2, 9 Hz, IH), 7.25 (d, J= 8 Hz, IH), 7.05 (d, J= 9 Hz, IH), 5.62 (br s IH), 5.40 (br s, IH), 3.96 (d, J= 8 Hz, IH), 3.38-3.46 (m, 4H), 1.81-2.03, (m, 9H), 1.86-1.94 (m, 4H), 1.76 (s, 6H), 1.63 (d, J= 12 Hz, 2H), 1.44 (d, J= 12 Hz, 2H). MS (ESI+) m/z 524, 526 (M+H)+.
Example 45
E-4-( {2-Methyl-2-[4-(methylsulfonyl)phenoxylpropanoyl> amino^adamantane- 1 -carboxamide
Example 45A
Example 45A was prepared according to the procedure outlined in Example 44C, substituting 4-(methanesulfonyl)-phenol for the product of Example 44B.
Example 45B
Example 45B was prepared according to the procedure outlined in Example 44D, substituting the product of Example 45A for the product of Example 44C.
Example 45 C Example 45C was prepared according to the procedure outlined in Example 44E, substituting the product of Example 45B for the product of Example 44D. Example 45D E-4-((2-Methyl-2-[4-(methylsulfonyl)phenoxylτ3ropanoyl>amino)adamantane-l-carboxamide
The title compound was prepared according to the procedure outlined in Example 44F, substituting the product of Example 45C for the product of Example 44E. The product had m.p. 217-219 0C. 1H NMR (500 MHz, CDCl3) δ ppm 7.85 (d, J= 8 Hz, 2H), 7.05 (d, J= 8 Hz, 2H), 6.66 (d, J= 7 Hz, IH), 5.65 (br s, IH), 5.49 (br s IH), 4.06 (d, J= 7 Hz, IH), 3.05 (s, 3H), 1.86-2.10 (m, 9H), 1.62 (s, 6H), 1.52 (s, 4H). MS (ESI+) m/z 435 (M+H)+.
Example 46 E-4-({2-Methyl-2-[2-(methylsulfonvDphenoxylpropanoyUamino)adamantane-l-carboxamide
Example 46A
2-Methyl-2-(2-methylsulfanyl-phenoxy)-propionic acid, ethyl ester 2-Methylsulfanyl-phenol (2.00 g, 14.29 mmol), 2-bromo-2-methyl-propionic acid, ethyl ester (28 g, 142 .8 mmol) and powdered K2CO3 (4.93 g, 35.7 mmol) were mixed (no solvent) and stirred at 105°C for 8 hrs. After cooling, water and CHCl3 were added. The CHCl3 was separated, dried (MgSO4) and concentrated. Xylene was added and concentrated in vacuo (4 times) to remove the bromo ester. The resulting oil was chromatographed on silica, eluting with CH2Cl2 to obtain the title compound (2.30 g, 63% yield).
Example 46B
2-Methyl-2-(2-methanesulfonyl-phenoxy)-propionic acid, ethyl ester To the product of Example 46A (1.00 g, 3.93 mmol) in CH2Cl2 (15 mL), was added, in portions, 3-chloroperoxybenzoic acid (3.00 g of 70%, 12.16 mmol) while stirring and cooling in a water bath. The mixture was stirred at 25°C for 20 hrs. Chloroform was added and the mixture was washed with KHCO3, Na2S2O3, and again with KHCO3. The solution was dried (Na2SO4), filtered and concentrated. Heptane was added and concentrated to obtain an oil that solidified (1.22 g, theory = 1.142 g).
Example 46C
2-Methyl-2-f2-methanesulfonyl-phenoxy>propionic acid The product of Example 46B (1.22 g) was dissolved in MeOH (8 mL) and treated with 50% NaOH (1.75 g, 21.27 mmol) and water (6 niL). The mixture was heated until all was soluble and stirred at 25°C for 1 hr. The solvents were removed in vacuo, water (6 mL) was added and the solution acidified with HCl. The mixture was extracted with CHCl3, dried (Na2SO4), filtered and concentrated in vacuo. The residue was crystallized from ether and heptane (1 :4) to yield the title compound (0.953 g), m.p. 114-116°C.
Example 46D
Example 46D was prepared according to the procedure outlined in Example 44D substituting the product of Example 46C for the product of Example 44C.
Example 46E
Example 46E was prepared according to the procedures outlined in Example 44E substituting the product of Example 46D for the product of Example 44D.
Example 46F E-4-({2-Methyl-2-[2-("methylsulfonyl)phenoxylpropanovUamino^adamantane-l-carboxamide
The title compound was prepared according to the procedure outlined in Example 44F, substituting the product of Example 46E for the product of Example 44E. 1H NMR (500 MHz, CDCl3) δ ppm 7.99 (dd, J= 7, 2 Hz, IH), 7.53 (m, IH)5 7.10-7.16 (m, 2H), 5.60 (br s IH), 5.40 (br s, IH), 3.95 (d, J= 8 Hz, IH), 3.27 (s, 3H), 1.80-1.96 (m, 9H), 1.55 (d, J =12 Hz, 2H), 1.37 (d, J= 12 Hz, 2H). MS (ESI+) m/z 435 (M+H)+.
Example 47 E-4-\(2- (4-Chloro-2-r(diethylaminoN)sulfonyllphenoxy> -2- methylpropanovDammol adamantane- 1 -carboxamide
Example 47A
Example 47A was prepared according to the procedure outlined in Example 44B, substituting diethylamine for pyrrolidine.
Example 47B Example 47B was prepared according to the procedure outlined in Example 44C, substituting the product of Example 47A for the product of Example 44B.
Example 47C Example 47C was prepared according to the procedure outlined in Example 44D, substituting the product of Example 47B for the product of Example 44C.
Example 47D
Example 47D was prepared according to the procedure outlined in Example 44E, substituting the product of Example 47C for the product of Example 44D.
Example 47E
E-4-1Y2- (4-Chloro-2-r(diethylamino)sulfonyl]phenoxy> -2- methylpropanoyDamino] adamantane- 1 -carboxamide
The title compound was prepared according to the procedure outlined in Example 44F, substituting the product of Example 47D for the product of Example 44E. The compound had m.p. 159-161°C. 1H NMR (400 MHz, CDCl3) δ ppm 7.83 (d, J= 2 Hz, IH), 7.34 (dd, J= 2, 9 Hz, IH), 7.05 (d, J= 8 Hz, IH), 6.98 (d, J= 9 Hz, IH), 5.58 (br s IH), 5.38 (br s, IH), 3.95 (d, J= 8 Hz, IH), 3.40 (q, J= 7 Hz, 4H)5 1.81-1.98, (m, 9H), 1.75 (s, 6H), 1.56 (d, J= 12 Hz, 2H), 1.42 (d, J= 12 Hz, 2H), 1.17 (t, J= 7 Hz, 6H). MS (ESI+) m/z 526, 528 (M+H)+.
Example 48 E-A-( (2-Methyl-2-[4-(pyrrolidin- 1 -ylsulfonvDphenoxylpropanovU ammo^adamantane- 1 - carboxamide
Example 48A l-(4-Methoxy-benzenesulfonylVpyrrolidine 4-Methoxy-benzenesulfonyl chloride (3.00 g, 14.52 mmol) was slowly added to a solution of pyrrolidine (5.15 g, 72.6 mmol) in CHCl3 (15 mL) with stirring at 00C. The reaction mixture was allowed to warm up to room temperature and then stirred for 1 hour. After that the reaction mixture was concentrated in vacuo. The residue was dissolved in toluene and washed with aqueous H3PO4 solution, and then aqueous KHCO3 solution. The organic phase was dried with Na2SO4, and filtered. The solvents were removed in vacuo and the residue crystallized from ether and heptane to provide the title compound (3.21 g, m.p. 88-89°C).
Example 48B l-(4-Hvdroxy-benzenesulfonyl)-pyrrolidine
The product of Example 48 A (3.21 g, 13.3 mmol) was dissolved in CH2Cl2 (30 mL), cooled to -78°C and treated with BBr3 (8.31 g, 3.26 mmol). The resulting dark red solution was stirred at 25°C for 4 min, then cooled to -78°C. Methanol (100 mL) was added slowly. The solution was concentrated in vacuo. Toluene was added to the crude and concentrated again. After adding more toluene, the solution was washed with water and concentrated in vacuo. The residue was dissolved in ether and extracted with NaOH (1.0 g) in water (8 mL). The aqueous layer was removed and stirred 15 minutes, then acidified with concentrated HCl. This mixture was extracted with toluene, dried (Na2SO4), filtered, concentrated in vacuo and the residue crystallized from ether and heptane (2:1) to provide the title compound (1.063 g, m.p. 122-125°C).
Example 48C
Example 48C was prepared according to the procedure outlined in Example 44C, substituting the product of Example 48B for the product of Example 44B.
Example 48D Example 48D was prepared according to the procedure outlined in Example 44D, substituting the product of Example 48C for the product of Example 44C.
Example 48E
Example 48E was prepared according to the procedure outlined in Example 44E, substituting the product of Example 48D for the product of Example 44D.
Example 48F E-4-( (2-Methyl-2-r4-(pyrrolidin-l -ylsulfonvDphenoxyipropanovU amino^adamantane- 1 - carboxamide
The title compound was prepared according to the procedure outlined in Example 44F, substituting the product of Example 48E for the product of Example 44E. The compound had m.p. 206-209°C. 1H NMR (500 MHz, CDCl3) δ pprn 7.76 (d, J= 8 Hz, 2H), 7.02 (d, J= 8 Hz, 2H), 6.71 (d, J= 8 Hz, IH), 5.65 (br s, IH), 5.54 (br s, IH), 4.067 (d, J= 8 Hz, IH), 3.20-3.26 (m, 4H), 1.86-2.06 (m, 9H), 1.77-1.82 (m, 4H), 1.61 (s, 6H), 1.51 (s, 4H). MS (ESI+) m/z 490 (M+H)+.
Example 49
2-(2-Chloro-4-fluorophenoxy)-N-[(E)-5-hydroxy-2-adamantyll-2-methylpropanamide
Example 49A
2-(4-Fluoro-2-chlorophenoxyV2-methyl-propionic acid 4-Fluoro-2-chlorophenol (6.0Og, 41.1 mmol) was reacted with 1,1,1 -trichloro-2- methyl-2-propanol hydrate (120 g, 12.70 mmol) as described in Example 44C to provide the title compound (6.075 g, 64% yield, m.p. 63-650C).
Example 49B 2-(2-Chloro-4-fluorophenoxy)-N-[rE)-5-hvdroxy-2-adamantyl1-2-methylpropanamide
The product of Example IA (175 mg, 1.05 mmol), 2-(4-fluoro-2-chlorophenoxy)-2- methyl-propionic acid (232 mg, 1.00 mmol), and TBTU (353 mg, 1.1 mmol) were dissolved in N,N-dimethylacetamide. Di-isopropylethylamine (258 mg, 2.0 mmol) was added and the mixture was stirred forlδ hrs at 25°C. After that the reaction mixture was concentrated in vacuo. The residue was dissolved in toluene and washed with aqueous H3PO4 solution, and then aqueous KHCO3 solution. The organic phase was dried with Na2SO4, and filtered. The solvents were removed in vacuo and the residue crystallized from ether and heptane to provide the title compound (262 mg, m.p. 177-179°C). 1H NMR (500 MHz, CDCl3) δ ppm 7.47 (d, J= 8 Hz, IH), 7.18 (dd, J= 2, 8 Hz, IH), 7.08 (dd, J= 5 Hz, 8 Hz, IH), 6.94 (m, IH), 4.07 (d, J= 8 Hz, IH), 2.12-2.21 (m, 3H), 1.91 (d, J= 11 Hz, 2H), 1.70-1.84 (m, 6H), 1.43-1.65 (m, 3H), 1.53 (s, 6H). MS (ESI+) m/z 382, 384 (M+H)+. Example 50
2-C2-Chloro-4-fluorophenoxyV2-nietliyl-N-r(E)-5-("2H-tetraazol-5-ylV2- adamantyllpropanamide
Example 5OA
Example 50A was prepared according to the procedure outlined in Example 44D, substituting the product of Example 49A for the product of Example 44C.
Example 5OB Example 50B was prepared according to the procedure outlined in Example 44E, substituting the product of Example 50A for the product of Example 44D.
Example 50C
E-4-["2-(2-Chloro-4-fluorophenoxyV2-methyl-propionylamino]-adamantane-l-carbonirrile Step A
E-4-[2-(2-Chloro-4-fluoro-phenoxy)-2-methyl-propionylamino]-adamantane-l- carboxylic acid amide was prepared according to the procedure outlined in Example 44F, substituting the product of Example 50B for the product of Example 44E. Step B The solution of the product of Step A (207 mg, 0.506 mmol) in dioxane (0.5 mL) and pyridine (100 mg) was treated with trifluoroacetic anhydride (167 mg, 0.795 mmol). The mixture was stirred 5 hr at 250C and concentrated in vacuo after adding toluene. More toluene was added and the solution was washed with dilute H3PO4, water, and aqueous KHCO3 solution respectively. After drying with Na2SO4, the solution was filtered, concentrated in vacuo and the residue crystallized from ether and heptane to yield the title compound (115 mg, m.p. 159-160°C).
Example 50D
2-(2-Chloro-4-fluorophenoxyV2-methyl-N-["fE)-5-(2H-tetraazol-5-ylV2- adamantyllpropanamide
A solution of the product of step B of Example 5OC (50 mg, 0.128 mmol), trimethyltin chloride (31 mg, 0.153 mmol) and NaN3 (10 mg, 0.153 mmol) in toluene (0.3 mL) was stirred and heated for 64 hrs in a sealed vial at 120°C. The mixture was cooled and 4N HCl in dioxane (1 mL) was added. After stirring 90 min at 25°C the solution was concentrated in vacuo. Water and HCl were added and the mixture was extracted with CHCl3, dried with Na2SO4, filtered, concentrated and treated with ether to provide the title compound (33 mg, m.p. 256-257°C). 1H NMR (400 MHz, DMSOd6) δ ppm 7.52 (d, J= 8 Hz, IH), 7.15-7.23 (m, 2H), 3.98 (d, J= 8 Hz IH), 1.98-2.12 (m, 9H), 1.90 (d, J= 13 Hz, 2H)5 1.60 (d, J= 13 Hz, 2H), 1.46 (s, 6H). MS (ESI+) m/z 434, 435 (M+H)+.
Example 51 2-(2-Chloro-4-fluorophenoxyV2-methyl-N-['('E)-5-fmethylthioV2-adamantyl1propanamide A solution of the product of Example 49B (150 mg, 0.392 mmol) in CF3COOH (750 mg) was treated with trifluoroacetic anhydride (375 mg, 1.78 mmol) for 5 min. Then, CF3COOH (1.68 g, 14.9 mmol) and NaSCH3 (549 mg, 7.8 mmols) were added to the 7 mL sealed tube. This mixture was heated at 12O0C for 20 hrs. After cooling, toluene was added, and the mixture concentrated in vacuo. More toluene was added and this was shaken with K2CO3 solution. The toluene layer was separated, dried (Na2SO4), concentrated and chromatographed in 4%EtOAc in DCM to give the title compound (132 mg, m.p. 100- 101°C). 1H NMR (400MHz, CDCl3) δ ppm 7.50 (d, J= 8 Hz, IH), 7.17 (dd, J= 2, 8 Hz, IH), 7.08 (dd, J= 5, 8Hz, IH), 6.93 (m, IH), 4.07 (d, J= 8 Hz, IH), 1.82-2.15 (m, 9H), 2.03 (s, 3H), 1.82 (d, J= 13 Hz, 2H), 1.59 (d, J= 13 Hz, 2H), 1.54 (s, 6H),.MS (ESI+) m/z 412, 414 (M+H)+.
Example 52
2-(2-Chloro-4-fluorophenoxyV2-methyl-N-[(E)-5-(methylsulfonylV2- adamantyl]propanamide
A solution of the product of Example 51 (100 mg, 0.235 mmol) in CH2Cl2 (1 ml) was treated with 3-chloroperbenzoic acid (180 mg, 70%, 1.05 mmol). After stirring for 17 hrs at 25°C, CHCl3 was added to the reaction mixture and the solution was extracted with KHCO3, Na2S2O3, and KHCO3. After drying (Na2SO4), filtered and concentrating, the residue was crystallized from heptane and ether to provide the title compound (89 mg, m.p. 172-1730C). 1H NMR (400MHz, CDCl3) δ ppm 7.55 (d, J= 8 Hz5 IH)5 7.18 (dd, J= 2, 8 Hz, IH), 7.09 (dd, J= 5, 8 Hz, IH)5 6.95 (m5 IH)5 4.09 (d, J= 8 Hz, IH), 2.76 (s, 3H), 2.07-2.25 (m, 9H), 1.90 (d, J= 13 Hz, 2H), 1.65 (d, J= 13 Hz, 2H), 1.54 (s, 6H). MS (ESI+) m/z 444, 446 (M+H)+.
Example 53 2-("2-Chloro-4-fluorophenoxyV2-methyl-N-r(E)-5-(methylsulfinylV2- adamantyllpropanamide
A-solution of the product of Example 51 (71 mg, 0.172 mmol) in acetic acid (75 mL) was prepared. Sodium perborate (NaBO3-H20, 18 mg, 0.18 mmol) was added and the mixture was stirred 16 hr at 25°C. Toluene was added. The mixture was concentrated and more toluene added. This was washed with K2CO3, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was crystallized from ether to get the title compound (44 mg, m.p. 134-135°C). 1H NMR (500MHz, CDCl3) δ ppm 7.58 (d, J= 8 Hz, IH), 7.19 (dd, J = 2, 8 Hz, IH), 7.10 (dd, J= 5, 8 Hz, IH), 6.95 (m, IH), 4.10 (d, J= 8 Hz, IH), 2.42 (s, 3H), 2.17-2.30 (m, 3H), 2.01 (d, J= 13 Hz, 2H), 1.82-2.05 (m, 6H), 1.55 (d, J- 13 Hz, 2H), 1.54 (s, 6H). MS (ESI+) m/z 428, 430 (M+H)+.
Example 54 N-[(E)-5-(Aminosulfonyl)-2-adamantyll-2-(4-chlorophenoxyV2-methylpropanamide
Example 54A
1 -Bromoadaman-4-one
5-Hydroxy-2-adamantanone (5.00 g, 30.1 mmol) was mixed with 48% hydrobromic acid (50 mL) and heated at 1000C for 48 hours (H. W. Geluk, J. L. M. A. Schlatmann, Tetrahedron 24: 5369-5377, 1968). Reaction diluted with water and extracted twice with ether. Combined extracts dried (Na2SO4), decanted, and evaporated under reduced pressure. The residue was purified on normal phase HPLC (silica gel, 5-10% ethyl acetate in hexane) to provide the title compound (4.19 g, 61%).
Example 54B l-Bromoadamantan-4-one ethylene ketal
The product of Example 54A (4.19 g, 18.3 mmol), ethylene glycol (2.05 mL, 36.6 mmol), and a catalytic amount of p-toluenesulfonic acid (20 mg) were dissolved in benzene (100 mL) and heated at reflux with a Dean-Stark apparatus attached for 16 hours (M. Xie, W. J. Ie Noble, J. Org. Chem. 54: 3836-3839, 1989). The reaction was cooled, washed with 2N sodium carbonate, water, and brine. The organic solution was dried (Na2SO4), filtered, and evaporated under reduced pressure to provide the title compound.
Example 54C
(Ii?, 2lSf)-l-Amino-2-indanol-N-4-toluene sulfonamide
(Ii?, 2IS)-Aminomdanol (5.00 g, 33.5 mmol) and ethyl acetate (75 mL) were added to a solution of sodium carbonate (6.89 g, 65.0 mmol) in water (30 mL) that had been stirring at room temperature for 20 minutes. After stirring this mixture for 20 minutes, a solution of p- toluenesulfonyl chloride (6.20 g, 32.5 mmol) in 1:1 THF/ethyl acetate (12 mL) was added drop-wise using an addition funnel over a period of 20 minutes (Z. Han, D. Krishnamurthy, P. Grover, Q. K. Fang, C. H. Senanayake, J. Am. Chem. Soc. 124: 7880-7881, 2002). Reaction stirred 16 hours at room temperature. Stirring was stopped, and the layers separated. The organic phase was washed with water, IN hydrochloric acid, and brine. The organic solution was dried (Na2SO4), filtered, and evaporated under reduced pressure to provide the title compound.
Example 54D (2R. 4R, 5SV3-(4-ToluenesulfonylV3.3a.8.8a-tetrahvdro-l-oxa-2-thia-3-aza- cyclopenta[a]indene-2-oxide and (2S. 4R. 5SV3-r4-ToluenesulfonylV3.3a.8.8a-tetrahvdro-l-oxa-2-thia-3-aza- cyclopenta|"a"|indene-2-oxide
A solution of the product of Example 54C (10.2 g, 33.5 mmol) at -450C in anhydrous THF (50 mL) was treated slowly, in one portion, with thionyl chloride (3.67 mL, 50.3 mmol). A solution of imidazole (6.84 g, lOlmmol) in anhydrous THF (50 mL) was then added drop- wise to this solution over 40 minutes using an addition funnel (Z. Han, D. Krishnamurthy, P. Grover, Q. K. Fang, C. H. Senanayake, J. Am. Chem. Soc. 124: 7880-7881, 2002). Reaction stirred two hours at -450C and was then quenched at -450C with saturated sodium bicarbonate. The mixture was then diluted with ethyl acetate and warmed to room temperature with stirring. The layers were allowed to separate and the organic phase was washed with water and brine. The organic solution was dried (Na2SO4), filtered, and evaporated under reduced pressure to provide the title compounds.
Example 54E
(Syf4-Adamantanone ethylene ketalVl -sulfuric acid-(lR, 2SVl-(4-toluenesulfonylaminoV indan-2-yl ester and (HV(4-Adamantanone ethylene ketalVl-sulfinic acid-dR, 2S)- 1 -(4- toluenesulfonylamino)-indan-2-yl ester
A 0.76M solution of Rieke Zinc (57 mL, 43.0 mmol) in THF was added at room temperature to a degassed solution under nitrogen containing the product of Example 54B (7.82 g, 28.6 mmol) in anhydrous THF (10 mL). Reaction stirred 16 hours at room temperature. More 0.76M Rieke Zinc (50 mL, 38.0 mmol) in THF was added, and reaction mixture stirred an additional 20 hours. This reaction mixture containing the zinc bromide was added drop-wise using a cannule to a -450C solution under nitrogen of the product of Example 54D (6.66 g, 19.1 mmol) in anhydrous THF (10 mL). Reaction stirred 16 hours at room temperature. Reaction mixture diluted with ethyl acetate, washed with brine, dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was purified on normal phase HPLC (silica gel, 30-40% ethyl acetate in hexane) to provide the title compound.
Example 54F l-f(S)-Ammosulfinyl)adamantan-4-one ethylene ketal and l-((R)-AminosulfinyDadamantan-
4-one ethylene ketal
A three-necked flask under argon equipped with a glass stir bar, a thermometer, a gas inlet, and an ammonia condenser (-780C) in a -5O0C bath was charged with anhydrous liquid ammonia (40 mL). A few crystals of iron nitrate nonahydrate (5 mg) were added to the ammonia, followed by portion-wise addition of lithium wire (650 mg, 93.7 mmol) in a controlled manner keeping the internal temperature at about -450C. When all the lithium was added and the blue solution became a grey suspension, the mixture was stirred for an additional two hours at -450C. The mixture was then cooled to -780C, and a solution of the product of Example 54E (7.00 g, 12.9 mmol) in anhydrous THF (30 mL) was added drop- wise over a period of 30 minutes. Reaction mixture stirred 2 hours at -780C and then quenched with saturated ammonium chloride. Reaction mixture allowed to warm to room temperature, and product extracted with ethyl acetate. Extracts washed with brine, dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was purified on normal phase HPLC (silica gel, 5% methanol in ethyl acetate) to provide the title compound (1.19 g, 36%).
Example 54G l-Aminosulfonyladamantan-4-one ethylene ketal
A solution of the product of Example 54F (1.19 g, 4.63 mmol) in anhydrous THF (10 mL) at room temperature was treated with a 2.5 wt. % solution of osmium tetroxide (0.35 niL) in 2-propanol and 4-methylmorpholine JV-oxide (0.55 g, 4.67 mmol). Reaction stirred at room temperature for 16 hours. Reaction diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), filtered, and evaporated under reduced pressure to provide the title compound.
Example 54H 1 - Aminosulfonyladamantan-4-one
A solution of the product of Example 54G (1.26 g, 4.63 mmol) in THF (15 mL) at room temperature was treated with IN hydrochloric acid (14 mL). Reaction heated at 6O0C for 16 hours. Reaction quenched with saturated sodium bicarbonate, and product extracted with 20% methanol in chloroform (2X) and 40% THF in DCM (2X). Extracts dried (Na2SO4), filtered, and evaporated under reduced pressure to provide the title compound (0.880 g, 82%).
Example 541
E-4-Amino-adamantane-l -sulfonic acid amide The title compound was prepared according to the procedure outlined in Example 7A substituting the product of Example 54H for 4-oxo-adamantane-l-carboxylic acid.
Example 54J
N-[(E)-5-(AmmosulfonylV2-adamantvn-2-('4-chlorophenoxyV2-methylpropanamide The product of Example 541 (100 mg, 0.44 mmol), 2-(4-chlorophenoxy)-2- methylpropionic acid (93 mg, 0.44 mmol), and TBTU (209 mg, 0.65 mmol) were mixed in DMF (2 mL) at room temperature for 10 minutes. N,iV-diisopropylethylamine (0.15 mL, 0.87 mmol) was added to this solution, and the reaction stirred 16 hours at room temperature. Reaction was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, IN phosphoric acid, and brine. Organic phase dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (20-30% ethyl acetate in hexane) to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.43 (d, J=6 hz, 1 H) 7.33 (d, J=8 Hz, 2 H) 6.91 (d, J=8 Hz5 2 H) 6.58 (s, 2 H) 3.79 (m, 1 H) 2.04 (bs, 2 H) 2.00-1.80 (m, 7 H) 1.71 (m, 2 H) 1.46 (s, 6 H) 1.35 (m, 2 H). MS (ESI+) m/z 427 (M+H)+.
Example 55
E-4-( { [ 1 -(4-Chlorophenoxy)cyclobutyr|carbonyU amino^adamantane- 1 -carboxamide
Example 55 A Ethyl l-(4-chlorophenoxy)cyclobutanecarboxylic acid A mixture of p-chlorophenol (621 mg, 4.83 mmol), ethyl 1- bromocyclobutanecarboxylate (1.0 g, 4.83 mmol) and potassium carbonate (1.33 g, 9.66 mmol) in DMF (14.5 ml) was stirred and heated to about 55-60 °C under a nitrogen atmosphere for about 18 hours. The solvent was removed under high vacuum, the residue was taken up in diethyl ether (50 ml) and was washed with water and brine (15 ml each). The organic layer was dried (MgSO4), and filtered. The solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2 : 1) as the mobile phase to provide 320 mg (26 %) of the title compound. MS (DCI): m/z 272 (M+NH4)+.
Example 55B
1 -(4-Chlorophenoxy)cvclobutanecarboxylic acid
To the product of Example 55A (320 mg, 1.26 mmol) was added glacial acetic acid (10 ml) followed by 5% aqueous hydrochloric acid (2.5 ml) and the mixture was heated to reflux for about 18 hours. The mixture was cooled and was evaporated to dryness. The residue was taken up in toluene and was evaporated to dryness two times to provide 250 mg (87 %) of the title compound. MS (DCI): m/z 244 (M+NH4)+. Example 55C E-4-({ri-(4-Chlorophenoxy)cvclobutyl1carbonyl>amino)adamantane-l- carboχylic acid methyl ester
A mixture of the product of Example 55B (207 mg, 0.81 mmol), the product of Example 7B (200 mg, 0.81 mmol), O-benzotriazol-l-yl-ΛζΛζN^N'-tetramethyluronium tetrafluoroborate (523 mg, 1.63 mmol) and iV,N-diisopropylethylamine (0.57 ml, 3.26 mmol) in DMF (11 ml) was stirred at ambient temperature under a nitrogen atmosphere for about 18 hours. The solvent was evaporated in high vacuum and the residue was purified by flash column chromatography on silica gel using hexanes/ethyl acetate (2 : 1) as the mobile phase to provide 240 mg (70 %) of the title compound. MS (DCI) m/z 418 (M+H)+.
Example 55D
E-4-({[l-(4-Chlorophenoxy)cvclobutyl1carbonyl>amino')adamantane-l- carboxylic acid To a solution of the product of Example 55C (240 mg, 0.57 mmol) in dioxane (8 ml) was added 2N aqueous hydrochloric acid (8 ml) and the mixture was heated to about 60 °C for about 18 hours. The mixture was cooled and concentrated in vacuo down to the water phase. The precipitate was filtered off and was dried under high vacuum to provide 200 mg (86 %) of the title compound. MS (DCI) m/z 404 (M+H)+.
Example 55E
E-4-( {[1 -(4-Chlorophenoxy)cyclobutyl]carbonyU amino)adamantane-l -carboxamide
A solution of the product of Example 55D (200 mg, 0.5 mmol), N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (380 mg, 2.0 mmol) and 1- hydroxybenzotriazole hydrate (217 mg, 1.61 mmol) in dichloromethane (17 ml) was stirred at ambient temperature under a nitrogen atmosphere for about 1 hour. A 0.5 M solution of ammonia in dioxane (9.9 ml, 4.95 mmol) was added and stirring was continued for about 2 hours. Ammonium hydroxide (8.5 ml) was added to the reaction mixture and stirring was continued for about 2 hours. The mixture was diluted with dichloromethane (55 ml), the layers were separated, the organic layer was dried (MgSO4), filtered, and was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel using dichloromethane/methanol (15 : 1) as the mobile phase to provide 113 mg (57 %) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.33-7.29 (m, 2H), 7.08-7.07 (m, IH), 6.92 (bs, IH), 6.74-6.70 (m, 2H)5 6.66 (bs, IH), 3.76-3.74 (m, IH), 2.68-2.62 (m, 2H), 2.33- 2.25 (m, 2H), 1.89-1.64 (m, HH), 1.37-1.34 (m, 2H), 1.22-1.19 (m, 2H). MS (ESI+) m/z 403 (M+H)+.
Example 56
4-[({[((E)-4-{[2-(4-Clilorophenoxy)-2-methylρropanoyllainino>-l- adamantvDmethyl] sulfonyl) amino^methyl]benzoic acid Step A
To a solution of the product of Example 36B (395 mg, 0.895 mmol) in DCM (8.9 mL) and DMF (1 drop) was added triphosgene (194 mg, 0.653 mmol) and triethylamine (0.125 mL, 0.895 mmol). The resulting reaction mixture was stirred at room temperature for 1.5 hours and then one half of the solution was added drop wise to a solution of methyl 4- (aminomethyl)-benzoate hydrochloride (67.6 mg, 0.447 mmol) and triethylamine (0.16 mL, 1.12 mmol) in DCM (1.0 mL). After stirring at room temperature overnight, the reaction was quenched with water and extracted with EtOAc. The organic layer was then rinsed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Step B
The product of Step A was dissolved in a mixture of THF, water, and ethanol and treated with excess NaOH. After stirring at room temperature overnight the reaction was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC using acetonitrile:10mM NH4OAc on YMC Guardpak column to provide the title compound (25 mg, 10%). 1H NMR (500 MHz, CDCl3) δ ppm 8.06 (d, J= 8.6 Hz, 2 H), 7.44 (d, J= 8.6 Hz, 2 H), 7.24 (d, J= 8.6 Hz, 2 H), 6.98 (d, J= 8.2 Hz, 1 H), 6.86 (d, J=8.6 Hz, 2 H), 4.92 (m, IH), 4.37 (d, J= 5.5 Hz, 2 H), 4.03 (m, 1 H), 2.83 (s, 2H), 1.50-2.17 (m, 11 H), 1.50 (s, 6H). MS (ESI+) m/z 575 (M+H)+.
Example 57 2-(4-ChlorophenoxyVN-|'(E)-5-(lH-imidazol-2-yl)-2-adamantyl1-2-methylpropanamide
The product of Example 33B (0.1 g, 0.266 mmol) and glyoxal (0.11 g, 40 wt% in water, 0.8 mmol) was dissolved in ammonia solution (6 mL, 7 N). The reaction vessel was sealed and stirred at room temperature for 1 day. The volatiles were evaporated and the residue was purified by reverse phase HPLC using CH3CN / 0.1% TFA in. water to provide the title compound as an oil. 1H NMR (300 MHz, CD3OD) δ ppm 1.48 - 1.59 (s, 6 H) 1.60 - 1.73 (m, 2 H) 1.77 - 1.94 (m, 2 H) 2.02 - 2.12 (m, 3 H) 2.12 - 2.27 (m, 6 H) 4.01 - 4.12 (m, 1 H) 6.88 - 7.02 (m, 2 H) 7.21 - 7.35 (m, 2 H) 7.44 - 7.49 (m, 2 H) 7.49 - 7.60 (m, 1 H). MS (ESl+) m/z 414.1 (M+H)+.
Example 58 (2E)-3-((E)-4-{[2-(4-ChlorophenoxyV2-metliylpropanoyllaminol-l-adamantvπacrylic acid
Example 58 A (2E)-3-((E)-4-{[2-(4-Chlorophenoxy)-2-methylpropanoyl1amino>-l-adamantyl)acrylic acid ethyl ester
To a cold (0°C) solution of triethyl phosphonoacetate (0.22 ml, 1.1 mmol) in DMΕ (1.0 mL) was added NaH (60% in oil, 42 mg, 1.1 mmol) under N2 flow. The reaction mixture was stirred for 10 minutes and a solution of the product of Example 33B (375 mg, lmmol) in DME (0.2 ml) was added slowly at 00C. It was allowed to warm up to room temperature and stirred for 5 hours. It was quenched with water and extracted with DCM 3 times. The combined organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure and purified by flash chromatography with 30% ethyl acetate / 70% hexane to provide the title compound, 350 mg (79%). 1H NMR (300 MHz, CDCl3) δ ppm 7.20 - 7.26 (m, 2 H), 6.94 - 7.03 (m, 1 H), 6.84 - 6.91 (m, 2 H), 6.80 (d, 1 H), 5.69 (d, 1 H), 4.19 (q, 2 H), 3.98 - 4.08 (m, 1 H), 1.91 - 2.08 (m, 3 H), 1.46 - 1.83 (m, 16 H)5 1.29 (t, 3 H). %). MS (ESI+) m/z 446 (M+H)+.
Example 58B (2E)-3-((E)-4- {J2-(4-ChlorophenoxyV2-methylpropanoyll amino) - 1 -adamantyDacrylic acid
To a solution of the product of Example 58A (45 mg, 0.1 mmol) in THF / water (0.1 ml / 0.05 ml) was added LiOH.H2O (26 mg, 0.6 mmol). It was stirred at room temperature overnight. It was acidified with IN HCl and extracted with DCM 3 times. The combined organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure and purified by flash chromatography with 30% ethyl acetate / 70% hexane to provide the title compound 35 mg (83%). 1H NMR (400 MHz, CDCl3) δ ppm 7.20 - 7.28 (m, 2 H), 6.96 - 7.04 (m, 1 H), 6.82 - 6.95 (m, 3 H), 5.70 (d, 1 H), 4.00 - 4.09 (m, 1 H), 1.93 - 2.08 (m, 3 H), 1.47 - 1.85 (m, 16 H). MS (ESI+) m/z 418 (M+H)+.
Example 59
(E)-A- \ (2-Methyl-2- { \ 5 -(I H-p yrazol- 1 - vDp yridin-2-yl] ox y) prop ano vD aminol adamantane- 1 - carboxamide
CuI (10.5 mg, 0.055 mmol), N,N,-dimethylglycine (11.3 mg, 0.109 mmol), K2CO3 (76 mg, 0.549 mmol), pyrazole (22 mg, 0.329 mmol), and the product of step C of Example 30B (80 mg, 0.183 mmol) was dissolved in DMSO (1 mL) and the resulting mixture was heated in Personal Chemistry's Emry Optimizer microwave instrument at 16O0C for 20 minutes. The mixture was diluted with EtOAc and filtered through a pad of silica and after evaporation the residue was purified by reverse phase HPLC using CH3CN / 0.1% TFA in water to give the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 1.40 - 1.64 (m, 4 H) 1.66 - 1.76 (m, 7 H) 1.77 - 1.87 (m, 3 H) 1.90 - 2.04 (m, 7 H) 3.93 (s, 1 H) 6.53 (dd, J= 2.54, 1.86 Hz, 1 H) 7.01 (d, J= 8.82 Hz, 1 H) 7.72 (d, J= 2.03 Hz, 1 H) 8.07 (dd, J= 8.99, 2.88 Hz, 1 H) 8.15 (d, J= 3.05 Hz, 1 H) 8.45 (d, J= 2.71 Hz, 1 H) 8.45 (d, J= 2.71 Hz, 1 H). MS (ESI+) m/z 424.2 (M+H)+.
Example 60
2-(4-Chlorophenoxy)-N-[(:E)-5-isoxazol-5-yl-2-adamantyl]-2-methylpropanamide
Example 6OA
2-(4-ChlorophenoxyV2-methyl-N-['(E)-5-propynoyl-adamantan-2-yl'l-propionamide Step A
Acetylenemagnesium chloride (8.22 mL, 0.5 M in THF, 4.11 mmol) was added dropwise to a stirred and cooled (-780C) solution of the product of Example 33B (0.514 g, 1.37 mmol) in dry THF. The resulting solution was warmed gradually to room temperature before it was quenched with saturated NH4Cl solution. The mixture was partitioned with Et2O and water. The organic phase was washed with brine, dried (MgSO4), filtered, and evaporated to give crude alcohol as an oil. Step B
Dess-Matin periodinane (1 g, 2.43 mmol) was added in one portion to a solution of the product of Step A (0.65 g, 1.62 mmol) in dry CH2Cl2. The resulting solution was stirred for 3 hours at room temperature before it was quenched with saturated NaHCO3 solution and Na2S2O3 solution. The mixture was stirred for 1 hour before the phases were separated. The organic phase was dried (Na2SO4), filtered, and the solvent was evaporated. The residue was purified over silica gel using 30% EtOAc in haxanes to provide the title compound as a yellow solid.
Example 6OB
2-(4-Chlorophenoxy)-N-[(E)-5-isoxazol-5-yl-2-adamantyll-2-methylpropanamide NH2OH.HC1 (0.23 g, 2.75 mmol) and K2CO3 (0.38 g, 2.75 mmol) was added to a solution of the product of Step B of Example 6OA (0.11 g, 0.275 mmol) in isopropanol. The. reaction was heated (8O0C) for 3 hours. The reaction mixture was diluted with EtOAc and filtered through a pad of Celite and after evaporation the residue was purified by reverse phase HPLC using CH3CN / 0.1% TFA in water to provide the title compound. 1H NMR (300 MHz, CD3OD) δ ppm 1.53 (s, 6 H) 1.65 (d, 2 H) 1.91 - 2.04 (m, 4 H) 2.11 (s, 6 H) 4.06 (d, J= 7.46 Hz5 1 H) 6.12 (d, J= 2.03 Hz, 1 H) 6.96 (d, J= 8.82 Hz, 2 H) 7.29 (d, J= 9.16 Hz, 2 H) 7.48 (d, J= 6.78 Hz, 1 H) 8.25 (d, J= 2.03 Hz, 1 H). MS (ESI+) m/z 415.1 (M+H)+.
Example 61
2-(4-ChlorophenoxyV2-methyl-N-{rE)-5-[C2-morpholin-4-ylethoxylmethyll-2- adamantyllpropanamide
A solution of the product of Example 33A (61 mg, 0.16 mmol) and 4-(2-Chloro- ethyl)-morpholine hydrochloride (36 mg, 0.19 mmol) in DMF (4 mL) was treated with sodium hydride (60%, 20.0 mg, 0.5 mmol) and was stirred at 1000C for 24 hours. Then the reaction mixture was cooled and filtered. The filtrate was concentrated under reduced pressure to provide crude title compound that was purified by reverse phase preparative HPLC using acetonitrile:10mM NH4OAc on YMC Guardpak column to afford the title compound. 1H NMR (500 MHz, CD3OD) δ ppm 7.41 (s, 1 H) 7.26 - 7.30 (m, 2 H) 6.93 - 6.96 (m, 2 H) 3.92 (s, 1 H) 3.66 - 3.72 (m, 4 H) 3.56 (t, J= 5.49 Hz, 2 H) 3.03 (s, 2 H) 2.59 (t, J= 5.49 Hz, 2 H) 2.52 - 2.57 (m, 4 H) 1.96 (d, J= 2.14 Hz, 2 H) 1.86 (s, 1 H) 1.72 (s, 1 H) 1.69 (s, 1 H) 1.67 (s, 4 H) 1.57 (d, J= 3.36 Hz, 2 H) 1.53 (s, 2 H) 1.51 (s, 6 H). MS (ESI+) m/z 491 (M+H)+. Example 62 N-[(E)-5-(Aminosulfonyl)-2-adaniantyll-2-(2-chlorophenoxyV2-methylpropanamide
Example 62A 2-(2-Chlorophenoxy)-2-methylpropionic acid
The title compound was prepared according to the procedure outlined in Example 44C substituting 2-chlorophenol for the product of Example 44B.
Example 62B N-[(E)-5-rAmmosulfonylV2-adamantyl]-2-(2-chlorophenoxyV2-methylpropanamide
The title compound was prepared according to the procedure outlined in Example 54J substituting the product of Example 62A for 2-(4-chlorophenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ ppm 7.61 (d, J=8 Hz, 1 H), 7.42 (dd, J=8 & 2 Hz, 1 H), 7.21 (m, 1 H), 7.13 (dd, J=8 & 2 Hz, 1 H), 7.05 (m, 1 H), 4.32 (s, 2 H), 4.09 (m, 1 H), 2.30-2.10 (m, 8 H), 1.90 (m, 2 H), 1.60 (m, 3 H), 1.46 (s, 6 H). MS (ESI+) m/z 427 (M+H)+.
Example 63 N-[(E)-5-(AmmosulfonylV2-adamantyll-2-methyl-2-(2-methylphenoxy)propanamide
Example 63A
2-Memyl-2-(2-methylphenoxy)propionic acid
The title compound was prepared according to the procedure outlined in Example 44C, substituting 2-methylphenol for the product of Example 44B.
Example 63B
N-[(E)-5-(Aminosulfonyl)-2-adamantvn-2-methyl-2-(2-methylphenoxy)propanamide
The title compound was prepared according to the procedure outlined in Example 54J substituting the product of Example 63 A for 2-(4-chlorophenoxy)-2-methylρropionic acid. 1H NMR (400 MHz, CDCl3) δ ppm 7.19 (dd, J=8 & 2 Hz, 1 H), 7.14 (d, J=8 Hz, 1 H), 7.09 (m, 1 H), 6.96 (m, 1 H), 6.86 (dd, J=8 & 2 Hz, 1 H), 4.33 (s, 2 H), 4.09 (m, 1 H), 2.28 (s, 3 H), 2.30-2.05 (m, 8 H), 1.71 (m, 2 H), 1.59 (m, 3 H), 1.52 (s, 6 H). MS (ESI+) m/z 407 (M+H)+. Example 64 N-[(E)-5-(Aminosulfonyl)-2-adamantyll-2-methyl-2-(4-methvbhenoxy')prot)anamide
Example 64A
2-Methyl-2-(4-methylphenoxy)propionic acid
The title compound was prepared according to the procedure outlined in Example 44C, substituting 4-methylphenol for the product of Example 44B.
Example 64B
N-[(E)-5-(AminosulfonylV2-adamantyl]-2-methyl-2-(4-methylphenoxy)propanamide
The title compound was prepared according to the procedure outlined in Example 54J substituting the product of Example 64A for 2-(4-chlorophenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ ppm 7.14 (d, J=8 Hz, 2 H), 7.08 (d, J=8 Hz, 2 H), 6.82 (d, J-8 Hz, 1 H), 4.46 (s, 2 H), 4.06 (m, 1 H), 2.31 (s, 3 H), 2.30-2.00 (m, 8 H), 1.72 (m, 2 H), 1.59 (m, 3 H), 1.49 (s, 6 H). MS (ESI+) m/z 407 (M+H)+.
Example 65
N-|TE)-5-(ΑmmosulfonylV2-adamantyll-2-methyl-2-r2- ftrifluoromethyl)phenoxy]propanamide
Example 65A
2-Methyl-2-(2-txifluoromethylphenoxy)propionic acid
The title compound was prepared according to the procedure outlined in Example 44C, substituting 2-trifluoromethylphenol for the product of Example 44B.
Example 65B N-[rE)-5-(AminosulfonylV2-adamantyll-2-methyl-2-r2- ftrifluoromethvDphenoxyjpropanamide The title compound was prepared according to the procedure outlined in Example 54J substituting the product of Example 65 A for 2-(4-chlorophenoxy)-2-methylρropionic acid. 1H NMR (400 MHz, CDCl3) δ ppm 7.61 (dd, J=8 & 2 Hz, 1 H), 7.45 (m, 1 H), 7.11 (m, 2 H), 7.01 (d, J=8 Hz, 1 H), 4.42 (s, 2 H), 4.06 (m, 1 H), 2.30-2.05 (m, 8 H), 1.70 (m, 3 H), 1.64 (s, 6 H), 1.55 (m, 2 H). MS (ESI+) m/z 461 (M+H)+.
Example 66 N4fE)-5-(AmmosulfonylV2-adamantyll-2-methyl-2-r2-
(trifluoromethoxy)phenoxy1propanamide
Example 66A
2-Methyl-2-(2-trifluoromethoxyphenoxy)propionic acid The title compound was prepared according to the procedure outlined in Example
44C, substituting 2-trifluoromethoxylphenol for the product of Example 44B.
Example 66B
N-[(E)-5-(AminosulfonylV2-adamantyll-2-methyl-2-r2- (Mfluoromethoxy)phenoxy]propanamide
The title compound was prepared according to the procedure outlined in Example 54J substituting the product of Example 66 A for 2-(4-chlorophenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ ppm 7.31 (dd, J=8 & 2 Hz, 1 H), 7.22 (m, 1 H), 7.18 (d, J=8 Hz, 1 H), 7.08 (m, 2 H), 4.39 (s, 2 H), 4.05 (m, 1 H), 2.30-2.05 (m, 8 H), 1.75 (m, 2 H), 1.59 (m, 3 H), 1.55 (s, 6 H). MS (ESI+) m/z 427 (M+H)+.
Example 67 N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-(2-chloro-4-fluorophenoxy)-2- methylpropanamide The title compound was prepared according to the procedure outlined in Example 54J substituting the product of Example 49 A for 2-(4-chlorophenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ ppm 7.54 (d, J=8 Hz, 1 H), 7.17 (m, 1 H), 7.08 (m, 1 H), 6.93 (m, 1 H), 4.26 (s, 2 H), 4.08 (m, 1 H), 2.35-2.05 (m, 8 H), 1.87 (m, 2 H), 1.60 (m, 3 H), 1.54 (s, 6 H). MS (ESI+) m/z 445 (M+H)+.
Biological Data: Measurement of Inhibition Constants: The ability of test compounds to inhibit human llβ-HSD-1 enzymatic activity in vitro was evaluated in a Scintillation Proximity Assay (SPA). Tritiated-cortisone substrate, NADPH co factor and titrated compound were incubated with truncated human 1 lβ-HSD-1 enzyme (24-287 AA) at room temperature to allow the conversion to Cortisol to occur. The reaction was stopped by adding a non-specific 11 β-HSD inhibitor, 1 Bβ-glycyrrhetinic acid. The tritiated Cortisol was captured by a mixture of an anti-cortisol monoclonal antibody and SPA beads coated with anti-mouse antibodies. The reaction plate was shaken at room temperature and the radioactivity bound to SPA beads was then measured on a β -scintillation counter. The 11-βHSD-l assay was carried out in 96-well microtiter plates in a total volume of 220 μl. To start the assay, 188 μl of master mix which contained 17.5 nM H-cortisone, 157.5 nM cortisone and 181 mM NADPH was added to the wells. In order to drive the reaction in the forward direction, 1 mM G-6-P was also added. Solid compound was dissolved in DMSO to make a 10 mM stock followed by a subsequent 10-fold dilution with 3% DMSO in Tris/EDTA buffer (pH 7.4). 22 μl of titrated compounds was then added in triplicate to the substrate. Reactions were initiated by the addition of 10 μl of 0. lmg/ml
E.coli lysates overexpressing 11 β-HSD- 1 enzyme. After shaking and incubating plates for 30 minutes at room temperature, reactions were stopped by adding 10 μl of 1 mM glycyrrhetinic acid. The product, tritiated Cortisol, was captured by adding 10 μl of 1 μM monoclonal anti- cortisol antibodies and 100 μl SPA beads coated with anti-mouse antibodies. After shaking for 30 minutes, plates were read on a liquid scintillation counter Topcount. Percent inhibition was calculated based on the background and the maximal signal. Wells that contained substrate without compound or enzyme were used as the background, while the wells that contained substrate and enzyme without any compound were considered as maximal signal. Percent of inhibition of each compound was calculated relative to the maximal signal and IC50 curves were generated. This assay was applied to 1 lβ-HSD-2 as well, whereby tritiated Cortisol and NAD+ were used as substrate and cofactor, respectively.
Compounds of the present invention are active in the 11-βHSD-l assay described above and show selectivity for human 11-β-HSD-l over human 1 l-β-HSD-2, as indicated in Table 1. Table 1. 11-β-HSD-l and 1 l-β-HSD-2 activity for representative compounds.
Figure imgf000101_0001
Figure imgf000102_0001
The data in Table 1 demonstrates that compounds A, B, C, D and E are active in the human llβ-HSD-1 enzymatic SPA assay described above and that the tested compound showed selectivity for llβ-HSD-1 over llβ-HSD-2. The llβ-HSD-1 inhibitors of this invention generally have an inhibition constant IC50 of less than 600 nM and preferably less than 50 nM. The compounds preferably are selective, having an inhibition constant IC50 against 1 lβ-HSD-2 greater than 1000 nM and preferably greater than 10,000 nM. Generally, the IC50 ratio for llβ-HSD-2 to llβ-HSD-1 of a compound is at least 10 or greater and preferably 100 or greater.
Metabolic Stability Incubation conditions:
Metabolic stability screen: each substrate (10 μM) was incubated with microsomal protein (0.1 - 0.5 mg/ml) in 5OmM potassium phosphate buffer (pH 7.4) in 48-Well plate. The enzyme reaction was initiated by the addition of ImM NADPH, then incubated at 370C in a Forma Scientific incubator (Marietta, OH, USA) with gentle shaking. The reactions were quenched by the addition of 800 μl of ACN/MeOH (1:1, v/v), containing 0.5 μM of internal standard (IS), after 30 min incubation. Samples were then filtered by using Captiva 96-Well Filtration (Varian, Lake Forest, CA, USA) and analyzed by LC/MS (mass spectrometry). Liver microsomal incubations were conducted in duplicate. LC/MS analysis:
The parent remaining in the incubation mixture was determined by LC/MS. The LC/MS system consisted of an Agilent 1100 series (Agilent Technologies, Waldbronn, Germany) and API 2000 (MDS SCIEX, Ontario, Canada). A Luna C8(2) (50 x 2.0 mm, particle size 3 μm, Phenomenex, Torrance, CA, USA) was used to quantify each compound at ambient temperature. The mobile phase consisted of (A): 10 mM NH4AC (pH 3.3) and (B): 100% ACN and was delivered at a flow rate of 0.2 ml/min. Elution was achieved using a linear gradient of 0-100% B over 3 min, then held 100% B for 4 min and returned to 100% A in 1 min. The column was equilibrated for 7 min before the next injection.
The peak area ratios (each substrate over IS) at each incubation time were expressed as the percentage of the ratios (each substrate over IS) of the control samples (0 min incubation). The parent remaining in the incubation mixture was expressed as the percentage of the values at 0 min incubation. The percentage turnover is calculated using the following equation (%turnover = 100%turnover - %parent remaining) and is recorded as the percentage turnover in the Table 2. Table 2. Microsomal metabolic stability.
Figure imgf000103_0001
Figure imgf000104_0001
Compounds A, B and E contain a substituted adamantane, whereas the adamantane ring of compound EE is unsύbstituted. The microsomal, metabolic, stability data in Table 2 demonstrates that substituted adamantane compounds of the present invention may exhibit an increase in metabolic stability compared to unsubstituted adamantane compounds which may lead to longer in vivo half lives and pharmacokinetic advantages over unsubstituted adamantanes.
Biochemical Mechanism Glucocorticoids are steroid hormones that play an important role in regulating multiple physiological processes in a wide range of tissues and organs. For example, glucocorticoids are potent regulators of glucose and lipid metabolism. Excess glucocorticoid action may lead to insulin resistance, type 2 diabetes, dyslipidemia, visceral obesity and hypertension. Cortisol is the major active and cortisone is the major inactive form of glucocorticoids in humans, while corticosterone and dehydrocorticosterone are the major active and inactive forms in rodents.
Previously, the main determinants of glucocorticoid action were thought to be the circulating hormone concentration and the density of glucocorticoid receptors in the target tissues, m the last decade, it was discovered that tissue glucocorticoid levels may also be controlled by 11 β-hydroxysteroid dehydrogenases enzymes (11 β-HSDs). There are two 11 β- HSD isozymes which have different substrate affinities and cofactors. The 1 lβ- hydroxysteroid dehydrogenases type 1 enzyme (1 lβ-HSD-1) is a low affinity enzyme with Km for cortisone in the micromolar range that prefers NADPH/NADP+ (nicotinamide adenine dinucleotide) as cofactors. 1 lβ-HSD-1 is widely expressed and particularly high expression levels are found in liver, brain, lung, adipose tissue and vascular smooth muscle cells. In vitro studies indicate that 1 lβ -HSD-I is capable of acting both as a reductase and a dehydrogenase. However, many studies have shown that it is predominantly a reductase in vivo and in intact cells. It converts inactive 11-ketoglucocorticoids (i.e., cortisone or dehydrocorticosterone) to active ll-hydroxyglucocorticoids (i.e., Cortisol or corticosterone) and therefore amplifies the glucocorticoid action in a tissue-specific manner.
With only 20% homology to 11 β-HSD- 1 , the 11 β-hydroxysteroid dehydrogenases type 2 enzyme (11 β-HSD-2) is a NAD+-dependent, high affinity dehydrogenase with a Km for Cortisol in the nanomolar range. 11 β-HSD-2 is found primarily in mineralocorticoid target tissues, such as kidney, colon and placenta. Glucocorticoid action is mediated by the binding of glucocorticoids to receptors, such as mineralocorticoid receptors and glucocorticoid receptors. Through binding to its receptor, the main mineralocorticoid aldosterone controls the water and salts balance in the body. However, the mineralocorticoid receptors have a high affinity for both Cortisol and aldosterone. 1 lβ-HSD-2 converts Cortisol to inactive cortisone, therefore preventing the non-selective mineralocorticoid receptors from being exposed to high levels of Cortisol. Mutations in the gene encoding 1 lβ-HSD-2 cause Apparent Mineralocorticoid Excess Syndrome (AME), which is a congenital syndrome resulting in hypokaleamia and severe hypertension. AME Patients have elevated Cortisol levels in mineralocorticoid target tissues due to reduced 11 β-HSD-2 activity. The AME symptoms may also be induced by administration of 1 lβ-HSD-2 inhibitor, glycyrrhetinic acid. The activity of 11 β-HSD-2 in placenta is probably important for protecting the fetus from excess exposure to maternal glucocorticoids, which may result in hypertension, glucose intolerance and growth retardation. Due to the potential side effects resulting from 1 lβ- HSD-2 inhibition, the present invention describes selective 11 β-HSD- 1 inhibitors.
Glucocorticoid levels and/or activity may contribute to numerous disorders, including Type II diabetes, obesity, dyslipidemia, insulin resistance and hypertension. Administration of the compounds of the present invention decreases the level of Cortisol and other llβ- hydroxysteroids in target tissues, thereby reducing the effects of glucucocrticoid activity in key target tissues. The present invention could be used for the treatment, control, amelioration, prevention, delaying the onset of or reducing the risk of developing the diseases and conditions that are described herein.
Since glucocorticoids are potent regulators of glucose and lipid metabolism, glucocorticoid action may contribute or lead to insulin resistance, type 2 diabetes, dyslipidemia, visceral obesity and hypertension. For example, Cortisol antagonizes the insulin effect in liver resulting in reduced insulin sensitivity and increased gluconeogenesis. Therefore, patients who already have impaired glucose tolerance have a greater probability of developing type 2 diabetes in the presence of abnormally high levels of Cortisol. Previous studies (B. R. Walker et al., J. of Clin. Endocrinology and Met., 80: 3155-3159, 1995) have demonstrated that administration of non-selective llβ-HSD-1 inhibitor, carbenoxolone, improves insulin sensitivity in humans. Therefore, administration of a therapeutically effective amount of an llβ-HSD-1 inhibitor may treat, control, ameliorate, delay, or prevent the onset of type 2 diabetes.
Administration of glucocorticoids in vivo has been shown to reduce insulin secretion in rats (B. Billaudel et al., Horm. Metab. Res. 11 : 555-560, 1979). It has also been reported that conversion of dehydrocorticosterone to corticosterone by 11 β-HSD-1 inhibits insulin secretion from isolated murine pancreatic β cells. (B. Davani et al., J. Biol. Chem., 275: 34841-34844, 2000), and that incubation of isolated islets with an llβ-HSD-1 inhibitor improves glucose-stimulated insulin secretion (H Orstater et al., Diabetes Metab. Res. Rev.. 21 : 359-366, 2005). Therefore, administration of a therapeutically effective amount of an 11 β-HSD-1 inhibitor may treat, control, ameliorate, delay, or prevent the onset of type 2 diabetes by improving glucose-stimulated insulin secretion in the pancreas.
Abdominal obesity is closely associated with glucose intolerance (C. T. Montaque et al., Diabetes, 49: 883-888, 2000), hyperinsulinemia, hypertriglyceridemia and other factors of metabolic syndrome (also known as syndrome X), such as high blood pressure, elevated VLDL and reduced HDL. Animal data supporting the role of 11 β-HSD-1 in the pathogenesis of the metabolic syndrome is extensive (Masuzaki, et ah. Science. 294: 2166-2170, 2001; Paterson, J.M., et al; Proc Natl. Acad. Sd. USA. 101: 7088-93, 2004; Montague and O'Rahilly. Diabetes. 49: 883-888, 2000). Therefore, administration of a therapeutically effective amount of an l lβ-HSD-1 inhibitor may treat, control, ameliorate, delay, or prevent the onset of obesity. Long-term treatment with an 11 β-HSD-1 inhibitor may also be useful in delaying the onset of obesity, or perhaps preventing it entirely if the patients use an 1 lβ- HSD-I inhibitor in combination with controlled diet, exercise, or in combination or sequence with other pharmacological approaches.
By reducing insulin resistance and/or maintaining serum glucose at normal concentrations and/or reducing obestity compounds of the present invention also have utility in the treatment and prevention of conditions that accompany Type 2 diabetes and insulin resistance, including the metabolic syndrome or syndrome X, obesity, reactive hypoglycemia, and diabetic dyslipidemia.
1 lβ-HSD-1 is present in multiple tissues, including vascular smooth muscle, where local glucocorticoid levels that are thought to increase insulin resistance, leading to reductions in nitric oxide production, and potentiation of the vasoconstrictive effects of both catecholamines and angiotensin II (M. Pirpiris et al., Hypertension, 19:567-574, 1992, C. Kornel et al., Steroids, 58: 580-587, 1993, B. R. Walker and B. C. Williams, Clin. Sci. 82:597-605, 1992; Hodge, G. et al Exp. Physiol 87: 1-8, 2002). High levels of Cortisol in tissues where the mineralocorticoid receptor is present may lead to hypertension, as observed in Cushing's patients (See, D. N. Orth, N. Engl. J. Med. 332:791-803, 1995, M. Boscaro, et al., Lancet, 357: 783-791, 2001, X. Bertagna, et al, Cushing's Disease. In: Melmed S., Ed. The Pituitary. 2nd ed. Maiden, MA: Blackwell; 592-612, 2002). Transgenic mice overexpressing 1 lβ-HSD-1 in liver and fat are also hypertensive, a phenotype believed to result from glucocorticoid activation of the renin angiotensin system (Paterson, J.M. et al, PNAS. 101: 7088-93, 2004; Masuzaki, H. et al, J. Clin. Invest. 112: 83-90, 2003). Therefore, administration of a therapeutically effective dose of an 11 β -HSD-I inhibitor may treat, control, ameliorate, delay, or prevent the onset of hypertension.
Cushing's syndrome is a life-threatening metabolic disorder characterized by sustained and elevated glucocorticoid levels caused by the endogenous and excessive production of Cortisol from the adrenal glands. Typical Cushingoid characteristics include central obesity, diabetes and/or insulin resistance, moon face, buffalo hump, skin thinning, dyslipidemia, osteoporosis, reduced cognitive capacity, dementia, hypertension, sleep deprivation, and atherosclerosis among others (Principles and Practice of Endocrinology and Metabolism. Edited by Kenneth Becker, Lippincott Williams and Wilkins Pulishers, Philadelphia, 2001; pg 723-8). The same characteristics can also arise from the exogenous administration of high doses of exogenous glucocorticoids, such as prednisone or dexamethasone, as part of an anti-inflammatory treatment regimen. Endogenous Cushings typically evolves from pituitary hyperplasia, some other ectopic source of ACTH, or from an adrenal carcinoma or nodular hyperplasia. Administration of a therapeutically effective dose of an llβ-HSD-1 inhibitor may reduce local glucocorticoid concentrations and therefore treat, control, ameliorate, delay, or prevent the onset of Cushing's disease and/or similar symptoms arising from glucocorticoid treatment.
1 lβ-HSD-1 is expressed in mammalian brain, and published data indicates that glucocorticoids may cause neuronal degeneration and dysfunction, particularly in the aged (de Quervain et al; Hum MoI Genet. 13: 47-52, 2004; Belanoff et «/. J. PsychiatrRes. 35: 127-35, 2001). Evidence in rodents and humans suggests that prolonged elevation of plasma glucocorticoid levels impairs cognitive function that becomes more profound with aging. (Issa, A.M. et al. J. Neurosci. 10: 3247-54, 1990; Lupien, SJ et al. Nat. Neurosci. 1 : 69-73, 1998; Yau, J.L.W. et al Proc Natl Acad Sd USA. 98: 4716-4712, 2001). Thekkapat έtf a/ has recently shown that 1 lβ-HSD-1 mRNA is expressed in human hippocampus, frontal cortex and cerebellum, and that treatment of elderly diabetic individuals with the nonselective HSD1/2 inhibitor carbenoxolone improved verbal fluency and memory (Proc Natl Acad Sd USA. 101: 6743-9, 2004). Additional CNS effects of glucocorticoids include glucocorticoid-induced acute psychosis which is of major concern to physicians when treating patients with these steroidal agents (Wolkowitz et ah; Ann NY Acad Sd. 1032: 191- 4, 2004). Conditional mutagenesis studies of the glucocorticoid receptor in mice have also provided genetic evidence that reduced glucocorticoid signaling in the brain results in decreased anxiety (Tranche, F. et al. (1999) Nature Genetics 23: 99-103). Therefore, it is expected that potent, selective llβ-HSD-1 inhibitors would treat, control, ameliorate, delay, or prevent the onset of cognitive decline, dementia, steroid-induced acute psychosis, depression, and/or anxiety.
In Gushing' s patients, excess Cortisol levels contributes to the development of hypertension, dyslipidemia, insulin resistance, and obesity, conditions characteristic of metabolic syndrome (Orth, D.N. et al N. Engl. J. Med. 332:791-803, 1995; Boscaro, M. et al., Lancet, 357: 783-791, 2001, Bertagna, X. et al, Cushing's Disease. In: Melmed S., Ed. The Pituitary. 2nd ed. Maiden, MA: Blackwell; 592-612, 2002). Hypertension and dyslipidemia are also associated with development of atherosclerosis. 1 lβ-HSD-1 knockout mice are resistant to the dyslipidemic effects of a high fat diet and have an improved lipid profile vs wild type controls (Morton N.M. et al, JBC, 276: 41293-41300, 2001), and mice which overexpress llβ-HSD-1 in fat exhibit the dyslipidemic phenotype characteristic of metabolic syndrome, including elevated circulating free fatty acids, and triclylgerides (Masuzaki, H., et al Science. 294: 2166-2170, 2001). Administration of a selective llβ- HSD-I inhibitor has also been shown to reduce elevated plasma triglycerides and free fatty acids in mice on a high fat diet, and significantly reduce aortic content of cholesterol esters, and reduce progression of atherosclerotic plaques in mice (Hermanowski-Vosatka, A. et al. J. Exp. Med. 202: 517-27, 2005). The administration of a therapeutically effective amount of an 11 β-HSD-1 inhibitor would therefore be expected to treat, control, ameliorate, delay, or prevent the onset of dyslipidemia and/or atherosclerosis.
Glucocorticoids are known to cause a variety of skin related side effects including skin thinning, and impairment of wound healing (Anstead, G. Adv Wound Care. 11 : 277- 85, 1998; Beer, et a!.; Vitam Harm. 59: 217-39, 2000). llβ-HSD-1 is expressed in human skin fibroblasts, and it has been shown that the topical treatment with the non-selective HSD1/2 inhibitor glycerrhetinic acid increases the potency of topically applied hydrocortisone in a skin vasoconstrictor assay (Hammami, MM, and Siiteri, PK. J. Clin. Endocrinol. Metab. 73: 326-34, 1991). Advantageous effects of selective llβ-HSD-1 inhibitors such as BVT.2733 on wound healing have also been reported (WO 2004/11310). High levels of glucocorticoids inhibit blood flow and formation of new blood vessels to healing tissues. In vitro and in vivo models of angiogenesis have shown that systemic antagonism with the glucocorticoid receptor RU-486 enchances angiogenesis in subcutaneous sponges as well as in mouse myocardium following coronary artery ligation (Walker, et al, PNAS, 102: 12165-70, 2005). llβ-HSD-1 knockout mice also showed enhanced angiogenesis in vitro and in vivo within sponges, wounds, and infarcted myocardium. It is therefore expected that potent, selective 11 β-HSD-1 inhibitors would treat, control, ameliorate, delay, or prevent the onset of skin thinning and/or promote wound healing and/or angiogenesis.
Although Cortisol is an important and well-recognized anti-inflammatory agent (J. Baxer, Pharmac. Ther., 2:605-659, 1976), if present in large amount it also has detrimental effects. In certain disease states, such as tuberculosis, psoriasis and stress in general, high glucocorticoid activity shifts the immune response to a humoral response, when in fact a cell based response may be more beneficial to patients. Inhibition of 11 β-HSD-1 activity may reduce glucocorticoid levels, thereby shifting the immuno response to a cell based response. (D. Mason, Immunology Today, 12: 57-60, 1991, G. A. W. Rook, Baillier's Clin. Endocrinol. Metab. 13: 576-581, 1999). Therefore, administration of 11 β-HSD-1 specific inhibitors could treat, control, ameliorate, delay, or prevent the onset of tuberculosis, psoriasis, stress, and diseases or conditions where high glucocorticoid activity shifts the immune response to a humoral response.
One of the more significant side effects associated with topical and systemic glucocorticoid therapy is glaucoma, resulting in serious increases in intraocular pressure, with the potential to result in blindness (Armaly et al; Arch Ophthalmol. 78: 193-7, 1967; Stokes et al; Invest Ophthalmol Vis Sd. 44: 5163-7, 2003; ). The cells that produce the majority of aqueous humor in the eye are the nonpigmented epithelial cells (NPE). These cells have been demonstrated to express 1 lβ-HSD-1, and consistent with the expression of 1 lβ-HSD-1, is the finding of elevated ratios of cortisohcortisone in the aqueous humor (Rauz et ah. Invest Ophthalmol Vis ScL 42: 2037-2042, 2001). Furthermore, it has been shown that patients who have glaucoma, but who are not taking exogenous steroids, have elevated levels of Cortisol vs. cortisone in their aqueous humor (Rauz et al. QJM. 96: 481-490, 2003.) Treatment of patients with the nonselective HSD1/2 inhibitor carbenoxolone for 4 or 7 days significantly lowered intraocular pressure and local Cortisol generation within the eye (Rauz et al; QJM. 96: 481-490, 2003.). It is therefore expected that potent, selective 1 lβ-HSD-1 inhibitors would treat, control, ameliorate, delay, or prevent the onset of glaucoma.
Glucocorticoids (GCs) are known to increase bone resorption and reduce bone formation in mammals (Turner et al. Calcif Tissue Int. 54: 311-5, 1995; Lane, NE et al
Med Pediatr Oncol 41: 212-6, 2003). llβ-HSD-1 niRNA expression and reductase activity have been demonstrated in primary cultures of human osteoblasts in homogenates of human bone (Bland et al; J. Endocrinol. 161: 455-464, 1999; Cooper et al; Bone, 23: 119-125, 2000). hi surgical explants obtained from orthopedic operations, llβ-HSD-1 expression in primary cultures of osteoblasts was found to be increased approximately 3-fold between young and old donors (Cooper et al; J. Bone Miner Res. 17: 979-986, 2002). Glucocorticoids, such as prednisone and dexamethasone, are also commonly used to treat a variety of inflammatory conditions including arthritis, inflammatory bowl disease, and asthma. These steroidal agents have been shown to increase expression of 1 lβ-HSD-1 mRNA and activity in human osteoblasts (Cooper et al; J. Bone Miner Res. 17: 979-986, 2002). These studies suggest that 1 lβ-HSD-1 plays a potentially important role in the development of bone-related adverse events as a result of excessive glucocorticoid levels or activity. Bone samples taken from healthy human volunteers orally dosed with the nonselective HSD1/2 inhibitor carbenoxolone showed a significant decrease in markers of bone resorption (Cooper et al; Bone. 27: 375-81, 2000). It is therefore expected that potent, selective 11 β-HSD-1 inhibitors would treat, control, ameliorate, delay, or prevent the onset of conditions of glucocorticoid-induced or age-dependent osteoporosis The following diseases, disorders and conditions can be treated, controlled, prevented or delayed, by treatment with the compounds of this invention: (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) lipid disorders, (5) hyperlipidemia, (6) hypertriglyceridemia, (9) hypercholesterolemia, (10) low HDL levels, (11) high LDL levels, (12), atherosclerosis and its sequelae, (13) vascular restensosis, (14) pancreatitis, (15) obdominal obesity, (16) neurodegenerative disease, (17) retinopathy, (18) nephropather, (19), neuropathy, (20) hypertension and other disorders where insulin resistance is a component, and (21) other diseases, disorders, and conditions that can benefit from reduced local glucocorticoid levels. Therapeutic compositions of the present compounds comprise an effective amount of the same formulated with one or more therapeutically suitable excipients. The term "therapeutically suitable excipient," as used herein, generally refers to pharmaceutically suitable, solid, semi-solid or liquid fillers, diluents, encapsulating material, formulation auxiliary and the like. Examples of therapeutically suitable excipients include, but are not limited to, sugars, cellulose and derivatives thereof, oils, glycols, solutions, buffers, colorants, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents and the like. Such therapeutic compositions may be administered parenterally, intracisternally, orally, rectally, intraperitoneally or by other dosage forms known in the art.
Liquid dosage forms for oral administration include, but are not limited to, emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may also contain diluents, solubilizing agents, emulsifying agents, inert diluents, wetting agents, emulsifiers, sweeteners, flavorants, perfuming agents and the like.
Injectable preparations include, but are not limited to, sterile, injectable, aqueous, oleaginous solutions, suspensions, emulsions and the like. Such preparations may also be formulated to include, but are not limited to, parenterally suitable diluents, dispersing agents, wetting agents, suspending agents and the like. Such injectable preparations may be sterilized by filtration through a bacterial-retaining filter. Such preparations may also be formulated with sterilizing agents that dissolve or disperse in the injectable media or other methods known in the art. The absorption of the compounds of the present invention may be delayed using a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the compounds generally depends upon the rate of dissolution and crystallinity. Delayed absorption of a parenterally administered compound may also be accomplished by dissolving or suspending the compound in oil. Injectable depot dosage forms may also be prepared by microencapsulating the same in biodegradable polymers. The rate of drug release may also be controlled by adjusting the ratio of compound to polymer and the nature of the polymer employed. Depot injectable formulations may also prepared by encapsulating the compounds in liposomes or microemulsions compatible with body tissues.
Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, gels, pills, powders, granules and the like. The drug compound is generally combined with at least one therapeutically suitable excipient, such as carriers, fillers, extenders, disintegrating agents, solution retarding agents, wetting agents, absorbents, lubricants and the like. Capsules, tablets and pills may also contain buffering agents. Suppositories for rectal administration may be prepared by mixing the compounds with a suitable non-irritating excipient that is solid at ordinary temperature but fluid in the rectum.
The present drug compounds may also be microencapsulated with one or more excipients. Tablets, dragees, capsules, pills and granules may also be prepared using coatings and shells, such as enteric and release or rate controlling polymeric and nonpolymeric materials. For example, the compounds may be mixed with one or more inert diluents. Tableting may further include lubricants and other processing aids. Similarly, capsules may contain opacifying agents that delay release of the compounds in the intestinal tract. Transdermal patches have the added advantage of providing controlled delivery of the present compounds to the body. Such dosage forms are prepared by dissolving or dispensing the compounds in suitable medium. Absorption enhancers may also be used to increase the flux of the compounds across the skin. The rate of absorption may be controlled by employing a rate controlling membrane. The compounds may also be incorporated into a polymer matrix or gel.
For a given dosage form, disorders of the present invention maybe treated, prophylatically treated, or have their onset delayed in a patient by administering to the patient a therapeutically effective amount of compound of the present invention in accordance with a suitable dosing regimen. In other words, a therapeutically effective amount of any one of compounds of formulas I thru DC is administered to a patient to treat and/or prophylatically treat disorders modulated by the 11-beta-hydroxy steroid dehydrogenase type 1 enzyme. The specific therapeutically effective dose level for a given patient population may depend upon a variety of factors including, but not limited to, the specific disorder being treated, the severity of the disorder; the activity of the compound, the specific composition or dosage form, age, body weight, general health, sex, diet of the patient, the time of admim'stration, route of administration, rate of excretion, duration of the treatment, drugs used in combination, coincidental therapy and other factors known in the art.
The present invention also includes therapeutically suitable metabolites formed by in vivo biotransformation of any of the compounds of formula I thru IX. The term "therapeutically suitable metabolite", as used herein, generally refers to a pharmaceutically active compound formed by the in vivo biotransform ation of compounds of formula I thru IX. For example, pharmaceutically active metabolites include, but are not limited to, compounds made by adamantane hydroxylation or polyhydroxylation of any of the compounds of formulas I thru IX. A discussion of biotransformation is found in Goodman and Gilman's, The Pharmacological Basis of Therapeutics, seventh edition, MacMillan Publishing Company, New York, NY, (1985). The total daily dose (single or multiple) of the drug compounds of the present invention necessary to effectively inhibit the action of 11-beta-hydroxysteroid dehydrogenase type 1 enzyme may range from about 0.01 mg/kg/day to about 50 mg/kg/day of body weight and more preferably about 0.1 mg/kg/day to about 25 mg/kg/day of body weight. Treatment regimens generally include administering from about 10 mg to about 1000 mg of the compounds per day in single or multiple doses.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed aspects will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

What is claimed,
1. A compound of formula (T)
Figure imgf000114_0001
(I), wherein
A1, A2, A3 and A4 are each individually selected from the group consisting of hydrogen, alkenyl, alkyl, alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, carboxyalkyl, carboxycycloalkyl, cyano, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, aryl, arylalkyl, aryloxyalkyl, arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocyclesulfonyl, halogen, haloalkyl, -NR5-[C(R6 R7)]n-C(O)-R8, -O-[C(R9R10)]p-C(O)-Rπ, -OR12, -S-alkyl, -S(O)-alkyl, -N(R13R14), -CO2R15, -C(O)-N(R16R17), -C(R18R19)-OR20,-C(R21R22)-N(R23R24), -C(^NOH)-N(H)2, -C(R18aR19a)-C(O)N(R23R24), -S(O)2-N(R25R26), and -C(R183R19a)- S(O)2-N(R25R26);
R18a and R19a are each independently selected from the group consisting of hydrogen and alkyl; n is O or l; p is O or 1;
D is a member selected from the group consisting of a -0-, -S-, -S(O)- and -S(O)2-;
E is a member selected from the group consisting of alkyl, alkoxyalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclealkyl, or R4 and E taken together with the atoms to which they are attached form a heterocycle;
R1 is a member selected from the group consisting of hydrogen and alkyl;
R2 is a member selected from the group consisting of hydrogen, alkyl and cycloalkyl;
R3 and R4 are each independently selected from the group consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl, or R3 and R4 taken together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R5 is a member selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, hydroxy, alkoxy, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
R6 and R7 are each independently selected from the group consisting of hydrogen and alkyl, or R6 and R7 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R8 is selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl and -N(R27R28);
R9 and R10 are each independently selected from the group consisting of hydrogen and alkyl, or R9 and R10 taken together with the atom to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle;
R11 is selected from the group consisting of hydroxy and -N(R29R30);
R12 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
R13 and R14 are each independently selected from the group consisting of hydrogen, alkyl, alkylsufonyl, aryl, arylalkyl, aryloxyalkyl, arylsulfonyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl and heterocyclesulfonyl;
R 5 is selected from the group consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl and heterocycleoxyalkyl;
R and R17 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkylsufonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl, hydroxy, and - alkyl-C(O)N(R201R202), or, R16 and R17 taken together with the atom to which they are attached form a heterocycle;
R and R are independently selected from the group consisting of hydrogen and alkyl;
R18, R19 and R20 are each independently selected from the group consisting of hydrogen, alkyl, aryl, arylalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl;
R21 and R22 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, cycloalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl and heterocyclesulfonyl;
R23 and R24 are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkoxy, alkylsulfonyl, aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl and hydroxy, or, R23 and R24 taken together with the atom to which they are attached form a ring selected from the group consisting of heteroaryl and heterocycle;
R25 and R26 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkylsufonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroaryloxy, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy, heterocyclesulfonyl, and hydroxy, or, R25 and R26 taken together with the atom to which they are attached form a heterocycle;
R and R are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkylsufonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl, heterocyclesulfonyl and hydroxy, or, R27 and R28 taken together with the atom to which they are attached form a heterocycle; and
R29 and R30 are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, alkylsufonyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, arylsulfonyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy, carboxycycloalkyl, cycloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl, heterocyclesulfonyl, and hydroxy, or, R29 and R30 taken together with the atom to which they are attached form a heterocycle; provided that, if R1 is hydrogen; then at least one of A1, A2, A3 and A4 is not hydrogen.
2. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen; and
R1 and R2 are hydrogen.
3. The compound according to claim 1 , wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; and R3 and R4 are hydrogen.
4. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; R3 and R4 are hydrogen; and D is -O-.
5. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 are hydrogen;
D is -O-; and
A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=N0H)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24).
6. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 are hydrogen;
D is -O-;
A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=N0H)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24); and
E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl, and cycloalkylalkyl.
7. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; R3 is hydrogen; and R4 is alkyl.
8. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; R3 is hydrogen; R4 is alkyl; and D is -O-.
9. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 is hydrogen;
R4 is alkyl;
D is -O-; and
A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=N0H)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24).
10. The compound, according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 is hydrogen;
R4 is alkyl;
D is -O-;
A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)- N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=N0H)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and -C(R21R22)-N(R23R24); and
E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylakyl, and cycloalkylalkyl.
11. The compound according to claim 1 , wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; and R3 and R4 are alkyl.
12. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; R3 and R4 are alkyl; and D is -O-.
13. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R and R are hydrogen; R3 and R4 are alkyl; D is -O-; and
A1 is selected from the group consisting of A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)-N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=NOH)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and - C(R21R22)-N(R23R24).
14. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 are alkyl;
D is -0-;
A1 is selected from the group consisting of A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)-N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -CC=NOH)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and - C(R21R22)-N(R23R24); and
E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl.
15. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; and
R3 and R4 taken together with the atoms to which they are attached form a ring selected from the group consisting of cycloalkyl and heterocycle.
16. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; and
R3 and R4 taken together with the atoms to which they are attached form a cycloalkyl ring.
17. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 taken together with the atoms to which they are attached form a cycloalkyl ring; and
D is -O-.
18. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 taken together with the atoms to which they are attached form a cycloalkyl ring;
D is -O- ; and
A1 is selected from the group consisting of A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)-N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=N0H)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and - C(R21R22)-N(R23R24).
19. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 taken together with the atoms to which they are attached form a cycloalkyl ring;
D is -O-;
A1 is selected from the group consisting of A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)-N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=N0H)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and - C(R21R22)-N(R23R24); and
E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl.
20. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; and
R3 and R4 taken together with the atoms to which they are attached form a heterocycle.
21. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 taken together with the atoms to which they are attached form a heterocycle; and D is -O-.
22. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 taken together with the atoms to which they are attached form a heterocycle;
D is -O-; and
A1 is selected from the group consisting of A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)-N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=NOH)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R185R19a)-S (O)2-N(R25R26), and - C(R21R22VN(R23R24).
23. The compound according to claim 1, wherein
A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R3 and R4 taken together with the atoms to which they are attached form a heterocycle; D is -O-;
A1 is selected from the group consisting of A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)-N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=NOH)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and - C(R21R22)-N(R23R24); and
E is selected from the group consisting of aryl, cycloalkyl, heteroaryl, heterocycle, arylalkyl and cycloalkylalkyl.
24. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen; and
R4 and E taken together with the atoms to which they are attached form a heterocycle.
25. The compound according to claim 1 , wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R4 and E taken together with the atoms to which they are attached form a heterocycle; and
D is -O-.
26. The compound according to claim 1, wherein A2, A3 and A4 are hydrogen;
R1 and R2 are hydrogen;
R4 and E taken together with the atoms to which they are attached form a heterocycle;
D is -O-; and
A is selected from the group consisting of A1 is selected from the group consisting of alkenyl, alkylsulfonyl, cyano, heteroaryl, heteroarylalkyl, -OR12, carboxyalkyl, -S-alkyl, -S(O)-alkyl, -C(R18R19)-OR20, -C(O)-N(R16R17), -C(R18aR19a)-C(O)N(R23R24), -C(=N0H)-N(H)2, -S(O)2-N(R25R26), -CO2R15, -C(R18aR19a)-S(O)2-N(R25R26), and - C(R21R22)-N(R23R24).
27. The compound according to claim 1, wherein A1 is selected from the group consisting of alkylsulfonyl, arylsulfonyl, cycloalkylsulfonyl, heteroarylsulfonyl and heterocyclesulfonyl;
A2, A3 and A4 are hydrogen; and D is -O-.
28. The compound according to claim 1, wherein D is -O-; A1 is -S(O)2-N(R25R26); and A2, A3 and A4 are hydrogen.
29. The compound according to claim 1, wherein A1 is -C(O)-N(R16R17) wherein R16 is selected from the group consisting of hydrogen and alkyl and R is selected from the group consisting of arylalkyl and heteroarylalkyl; D is — O-; and A2, A3 and A4 are hydrogen.
30. The compound according to claim 1, that is a member selected from the group consisting of
E-4-[(2-methyl-2-phenoxypropanoyl)amino] adamantane- 1 -carboxamide;
E-4-[(2-methyl-2-{[4-(trifluoromethyl)benzyl]oxy}propanoyl)amino]adamantane-l- carboxamide;
E-4-({2-methyl-2-[(2-methylcyclohexyl)oxy]propanoyl}amino)adamantane-l- carboxylic acid;
E-4-({2-methyl-2-[(3-methylcyclohexyl)oxy]propanoyl}amino)adamantane-l- carboxylic acid;
E-A- { [2-(cycloheptyloxy)-2-methylpropanoyl] amino} adamantane- 1 -carboxylic acid;
E-4- { [2-(cyclohexylmethoxy)-2-methylpropanoyl] amino } adamantane- 1 -carboxylic acid;
E-4- {[2-(4-chlorophenoxy)-2-methylρropanoyl]amino} adamantane-1 -carboxylic acid;
E-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxamide;
E-4-({2-methyl-2-[(4-methylcyclohexyl)oxy]propanoyl}amino)adamantane-l- carboxamide;
E-4-[(2-phenoxypropanoyl)amino]adamantane-l-carboxamide;
E-4- { [2-methyl-2-(2-methylphenoxy)propanoyl] amino} adamantane-1 -carboxylic acid;
E-4-{[2-methyl-2-(4-methylphenoxy)propanoyl3amino}adamantane-l-carboxylic acid;
E-4-{[2-(2-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxylic acid;
E-4-{[2-(2-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxamide;
E-4- {[2-(4-methoxyphenoxy)-2-methylpropanoyl] amino} adamantane- 1 -carboxamide;
E-4-({2-methyl-2-[3-(trifluoromethyl)phenoxy]propanoyl}amino)adamantane-l- carboxamide;
E-4-{[2-(3-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxamide;
E-2-(4-Chloro-phenoxy)-N-(5-hydroxy-adamantan-2-yl)-2-methyl-propionamide;
E-{[2-Methyl-2-(4-methylphenoxy)propanoyl]amino}adamantane-l-carboxamide;
E-4- { [2-(3-Chlorophenoxy)-2-methylpropanoyl] amino} adamantane- 1 -carboxamide;
E-4-{ {2-Methyl-2-[4-(trifluoromethoxy)phenoxy]propanoyl} amino)adamantane- 1 - carboxamide;
E-4- {[2-(3-Bromophenoxy)-2-methylpropanoyl]amino} adamantane- 1 -carboxylic acid;
4-( {[({E)-4- {[2-(4-Chloroρhenoxy)-2-methylpropanoyl]amino} -1 - adamantyl)carbonyl]amino}methyl)benzoic acid;
E-4- { [2-(2,3 -Dimemylphenoxy)-2-methylpropanoyl] amino } adamantane- 1 -carboxylic acid; tert-Butyl 4-(2- { [(E)-5 -(aminocarbonyl)-2-adamantyl] amino} -1,1 -dimethyl-2- oxoethoxy)phenylcarbamate;
E-N-[4-(Aminocarbonyl)benzyl]-4-{[2-(4-chlorophenoxy)-2- methylpropanoyl]amino} adamantane- 1 -carboxamide;
E-N-[4-(Aminocarbonyl)methyl]-4-{[2-(4-chlorophenoxy)-2- methylpropanoyl]amino}adamantane-l-carboxamide;
3 -( { [((E)-4- { [2-(4-Chlorophenoxy)-2-methylpropanoyl] amino } - 1 - adamantyl)carbonyl]amino}methyl)benzoic acid;
E-4-{ {2- [(5-Bromopyridin-2-yl)oxy] -2-methylpropanoyl} amino)adamantane- 1 - carboxamide;
E-4-{[2-(2-Cyanophenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxamide;
E-4-{[2-(4-Hydroxyphenoxy)-2-methylpropanoyl]ammo}adamantane-l-carboxamide;
{{E)-4- {[2-(4-Chlorophenoxy)-2-methylpropanoyl] amino} - 1 -adamantyl)acetic acid;
N-[(E)-5-(2-Amino-2-oxoethyl)-2-adamantyl]-2-(4-chloropb.enoxy)-2- methylpropanamide;
2-(4-Chloroρhenoxy)-2-methyl-N-[(E)-5-(2H-tetraazol-5-ylmethyl)-2- adamantyl]propanamide;
N-{(E)-5-[(Aminosulfonyl)methyl]-2-adaniantyl}-2-(4-chlorophenoxy)-2- methylpropanamide;
N-{(E)-5-[(Z)-Amino(hydroxyimmo)niethyl]-2-adamantyl}-2-(4-chloropheiioxy)-2- methylpropanamide;
£-N-[4-(Aminosulfonyl)benzyl]-4-{[2-(4-chlorophenoxy)-2- methylpropanoyl]amino}adamantane-l-carboxamide;
E-A- { [2-(4-Chlorophenoxy)-2-methylpropanoyl] amino } -N-(4- {[(methylsulfonyl)amino]carbonyl}benzyl)adamantane-l-carboxamide;
£'-4-({2-[(4-Chlorophenyl)thio]-2-methylpropanoyl}ammo)adamantane-l-carboxylic acid;
E-4-( {2- [(4-Methoxyphenyl)thio] -2-methylpropanoyl} amino)adamantane- 1 - carboxamide amide;
E-4-({2-[(4-Methoxyphenyl)sulfinyl]-2-methylpropanoyl}amino)adamantane-l- carboxamide;
E-4-({2-[(4-Methoxyphenyl)sulfonyl]-2-methylpropanoyl}amino)adamantane-l- carboxamide;
E-4-({2-[4-Chloro-2-(pyrrolidin-l-ylsulfonyl)phenoxy]-2- methylpropanoyl} amino)adamantane- 1 -carboxamide;
E-4-( {2-Methyl-2-[4-(methylsulfonyl)phenoxy]propanoyl} amino)adamantane- 1 - carboxamide;
E-4-({2-Methyl-2-[2-(methylsulfonyl)phenoxy]propanoyl}amino)adamantane-l- carboxamide;
E-4-[(2- {4-Chloro-2-[(diethylamino)sulfonyl]phenoxy} -2- methylρropanoyl)amino]adamantane-l-carboxatnide;
E-4-( {2-Methyl-2-[4-(pyrrolidin- 1 - ylsulfonyl)phenoxy]propanoyl} amino)adamantane- 1 -carboxamide;
2-(2-Chloro-4-fluorophenoxy)-N-[(E)-5-hydroxy-2-adamantyl]-2- methylpropanamide;
2-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(2H-tetraazol-5-yl)-2- adamantyl]propanamide;
2-(2-Chloro-4-fluoroρhenoxy)-2-methyl-N-[(J5)-5-(inethylthio)-2- adamantyl]propanamide;
2-(2-Chloro-4-fluoroρhenoxy)-2-metliyl-N-[(E)-5-(methylsulfonyl)-2- adamantyljpropanamide;
2-(2-Chloro-4-fluoroρhenoxy)-2-methyl-N-[(E)-5-(methylsulfmyl)-2- adamantyljpropanamide;
N-[(-^-5-(Aminosulfonyl)-2-adamantyl]-2-(4-chlorophenoxy)-2-methylpropanamide;
E-4-( { [ 1 -(4-Chlorophenoxy)cyclobutyl]carbonyl} amino)adatnantane- 1 -carboxamide;
4-[( {[((E)-4- {[2-(4-Chlorophenoxy)-2-methylpropanoyl]amino} -1 - adamantyl)methyl] sulfonyl} amino)methyl]benzoic acid;
2-(4-Chlorophenoxy)-N-[(E)-5-(lH-imidazol-2-yl)-2-adamantyl]-2- methylpropanamide;
(2E)-3-((E)-4-{[2-(4-Chlorophenoxy)-2-methylρroρanoyl]amino}-l- adamantyl)acrylic acid;
(E)-4-[(2-Methyl-2-{[5-(lH-pyrazol-l-yl)pyridin-2- yl]oxy}propanoyl)amino]adamantane-l-carboxamide;
2-(4-Chlorophenoxy)-N-[(E)-5-isoxazol-5-yl-2-adamantyl]-2-methylpropanamide;
2-(4-Chlorophenoxy)-2-methyl-N-{(E)-5-[(2-morρholin-4-ylethoxy)inethyl]-2- adamantyljpropanamide;
N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-(2-chlorophenoxy)-2-methylpropanamide;
N- [(E)S -(Aminosulfonyl)-2-adamantyl] -2-methyl-2-(2-methylphenoxy)propanamide;
N-[(-5^-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-(4-methylphenoxy)propanamide;
N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-[2- (trifluoromethyl)phenoxy]propanamide;
N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-methyl-2-[2- (trifluoromethoxy)phenoxy]propanamide;
N-[(E)-5-(Aminosulfonyl)-2-adamantyl]-2-(2-chloro-4-fluoroρhenoxy)-2- methylpropanamide;
E-4- {[2-(2-chlorophenoxy)-2-methyl-3-phenylpropanoyl]amino} adamantane-1 - carboxamide;
2-(4-chlorophenoxy)-N-[(E)-5-hydroxy-2-adamantyl]-2-methylpropanamide; E-4-({2-methyl-2-[(5-morpholin-4-ylρyridin-2-yl)oxy]propanoyl}animo)adamantane- 1-carboxamide;
£J-4-{[2-methyl-2-(pyridin-2-yloxy)propanoyl]amino}adamantane-l-carboxamide;
2-(4-chlorophenoxy)-2-methyl-N-{ E)-5-[(methylamino)sulfonyl]-2- adamantyljpropanamide;
3-((E)-4-{[2-(4-chlorophenoxy)-2-methylpropanoyl]amino}-l-adamantyl)ρropanoic acid;
2-(4-chlorophenoxy)-N-{(E)-5-[(dimethylamino)sulfonyl]-2-adamantyl}-2- methylpropanamide;
£-4-[(2-{[5-(lH-imidazol-l-yl)pyridin-2-yl]oxy}-2- methylρropanoyl)amino]adamantane- 1 -carboxamide;
2-(4-chloroρhenoxy)-2-methyl-N-[(E)-5-(lH-pyrazol-3-yl)-2- adamantyl]propanamide;
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(3-chloropb.enoxy)-2-methylpropananiide;
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-methyl-2-(3-methylpb.enoxy)propanamide;
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(2-metlioxyphenoxy)-2- methylpropanamide;
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(3-methoxyphenoxy)-2- methylpropanamide;
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-methoxyphenoxy)-2- methylpropanamide;
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-cyanophenoxy)-2-methylpropanamide;
E-4-{[2-methyl-2-(2-methylρhenoxy)propanoyl]amino}adamantane-l-carboxamide;
E-4-{[2-methyl-2-(3-methylρhenoxy)propanoyl]amino}adamantane-l-carboxamide;
E-4-[(2-methyl-2-{[(lS,2S)-2-methylcyclohexyl]oxy}propanoyl)amino]adamantane- 1-carboxylic acid;
E-4-( {2-methyl-2-[(2-methylcyclohexyl)oxy]propanoyl} amino)adamantane- 1 - carboxamide
E-4- { [2-(cycloheptyloxy)-2-methylpropanoyl] amino} adamantane- 1 -carboxamide;
E-A- {[2-(cyclohexylmethoxy)-2-methylpropanoyl]amino} adamantane- 1- carboxamide;
E-4-( {2-methyl-2- [(3 -methylcyclohexyl)oxy]propanoyl} amino)adamantane- 1 - carboxamide;
E-4- {[2-(2-chlorophenoxy)-2-raethylpropanoyl]amino} adamantane-1 -carboxamide;
4- { [( {(E)-4- [(2-methyl-2-phenoxypropanoyl)amino] - 1 - adamantyl} carbonyl)amino]methyl}benzoic acid;
E-4-({2-[(4,4-dimethylcyclohexyl)oxy]-2-methylpropanoyl}amino)adamantane-l- carboxylic acid;
E-4- {[2-methyl-2-(l ,2,3,4-tetrahydronaρhthalen-2- yloxy)propanoyl]amino}adaniantane-l-carboxylic acid;
E-4-{[2-(4-bromophenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxylic acid;
E-4- { [2-methyl-2-( 1 -naphthyloxy)propanoyl] amino } adamantane- 1 -carboxylic acid;
E-4-{[2-(2,3-dichlorophenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxylic acid;
E-4- { [2-(2,4-dichlorophenoxy)-2-methylpropanoyl] amino } adamantane- 1 -carboxylic acid;
E-4-{[2-(2,5-dichlorophenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxylic acid;
E-4- { [2-(2,4-dimethylphenoxy)-2-methylpropanoyl] amino } adamantane- 1 -carboxylic acid;
E-4-{[2-(2,5-dimethylph.enoxy)-2-methylpropanoyl]amino}adamantane-l-carboxylic acid;
E-4- { [2-methyl-2-(2-naphthyloxy)propanoyl] amino} adamantane- 1 -carboxylic acid;
E-4- { [2-(4-bromo-2-fluorophenoxy)-2-methylpropanoyl] amino } adamantane- 1 - carboxylic acid;
E-4-({2-methyl-2-[(7-methyl-2,3-dihydro-lH-inden-4- yl)oxy]propanoyl}amino)adamantane-l-carboxylic acid;
E-4-{[2-(4-bromo-2-chlorophenoxy)-2-methylpropanoyl]amino}adamantane-l- carboxylic acid;
E-4- { [2-( 1 , 1 '-biphenyl-3 -yloxy)-2-methylpropanoyl] amino } adamantane- 1 -carboxylic acid;
E-4- { [2-(2-bromophenoxy)-2-methylpropanoyl] amino} adamantane- 1 -carboxylic acid; E-N-[4-(ammocarbonyl)berizyl]-4-[(2-methyl-2- phenoxypropanoyl)amino] adamantane- 1 -carboxamide;
E-4- {[2-(4-chlorophen.oxy)-2-methylpropan.oyl]ammo} -N-(I s3-thiazol-5- ylmethyl)adamantane-l-carboxamide;
E-4- {[2-(4-chlorophenoxy)-2-methylpropanoyl]amino} -N-(pyridin-4- ylniethyl)adamantane-l -carboxamide;
E-4-{[2-(4-aminophenoxy)-2-methylpropanoyl]amino}adamantane-l-carboxamide;
E-4-( {2-methyl-2-[2-(trifluoromethoxy)phenoxy]propanoyl} amino)adamantane- 1 - carboxamide;
E-4-( {2-methyl-2-[2-(trifluoromethyl)phenoxy]propanoyl} amino)adamantane- 1 - carboxamide;
E-4-( {2-methyl-2-[4-(ρyrrolidin- 1 - ylsulfonyl)phenoxy]propanoyl} amino)adamantane- 1 -carboxamide;
2-(2-chloro-4-fluorophenoxy)-N-[(E)-5-hydroxy-2-adamantyl]-2-methylpropanamide;
2-(2-chloro-4-fluorophenoxy)-N-[(£)-5-cyano-2-adamantyl]-2-methylpropanamide;
E'-4-[(2-methyl-2-{4-[(trifluoroacetyl)amino]phenoxy}propanoyl)ammo] adamantane- 1 -carboxamide;
E-4-{[2-(3-bromo-4-methoxyphenoxy)-2-methylpropanoyl]amino}adamantane-l- carboxamide;
E-4-{[2-(2,5-dibromo-4-methoxyphenoxy)-2-methylρropanoyl]amino}adamantane-l- carboxamide;
E-4-{[2-(2-bromo-4-methoxyphenoxy)-2-methylpropanoyl]ammo}adamantane-l- carboxamide;
E-4-{[2-(2-chloro-4-fluorophenoxy)-2-methylpropanoyl]amino}-N,N- dimethyladamantane-1 -carboxamide;
2-(4-chlorophenoxy)-N-((E)-5-{[(4-methoxy-6-methylpyrimidin-2-yl)amino]methyl}- 2-adamantyl)-2-methylpropanamide;
E-4- {[2-(4- {[(tert-butylamino)carbonyl]amino}phenoxy)-2- meth.ylpropanoyl]amino } adamantane- 1 -carboxamide ; ethyl 4-(2- { [(E)-5 -(aminocarbonyl)-2-adamantyl] amino } - 1 , 1 -dimethyl-2- oxoethoxy)phenylcarbamate;
E-4-[(2-methyl-2-{4-[(propylsulfonyl)amino]phenoxy}propanoyl)amino] adamantane- 1 -carboxamide;
E-4-[(2-{4-[(3,3-dimethylbutanoyl)amino]phenoxy}-2-methylpropanoyl)amino] adamantane- 1 -carboxamide;
E-4-{[2-methyl-2-(phenylsulfinyl)propanoyl]amino}adamantane-l-carboxylic acid;
EA- {[2-methyl-2-(phenylsulfonyl)propanoyl]amino} adamantane-1-carboxylic acid;
N-[(E)-5-cyano-2-adamantyl]-2-[(4-methoxyphenyl)sulfonyl]-2-methylpropanamide;
2-[(4-methoxyphenyl)sulfonyl]-2-methyl-N-[(E)-5-(2H-tetraazol-5-yl)-2- adamantyljpropanamide; and
E-4-({2-[4-(benzyloxy)phenoxy]-2-methylpropanoyl}amino)adamantane-l- carboxamide.
31. A method of inhibiting 11 -beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
32. A method of treating disorders in a mammal by inhibiting 11 -beta-hydroxysteroid dehydrogenase Type I enzyme, comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
33. A method of treating non-insulin dependent type 2 diabetes in a mammal by inhibiting 11 -beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
34. A method of treating insulin resistance in a mammal by inhibiting 11 -beta- hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
35. A method of treating obesity in a mammal by inhibiting 11 -beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
36. A method of treating lipid disorders in a mammal by inhibiting 11-beta- hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
37. A method of treating metabolic syndrome in a mammal by inhibiting 11-beta- hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
38. A method of treating diseases and conditions that are mediated by excessive glucocorticoid action in a mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising administering to a mammal, a therapeutically effective amount of the compound of formula (I) of claim 1.
39. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I) of claim 1 in combination with a pharmaceutically suitable carrier.
PCT/US2006/000210 2005-01-05 2006-01-05 Adamantyl derivatives as inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme WO2006074244A2 (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
AU2006204017A AU2006204017B2 (en) 2005-01-05 2006-01-05 Adamantyl derivatives as inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
EP06717418A EP1846363B1 (en) 2005-01-05 2006-01-05 Adamantyl derivatives as inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
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KR1020077017997A KR101496190B1 (en) 2005-01-05 2006-01-05 Adamantyl derivatives as inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
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AT06717418T ATE555081T1 (en) 2005-01-05 2006-01-05 ADAMANTYL DERIVATIVES AS INHIBITORS OF THE 11-BETA-HYDROXYSTEROID DEHYDROGENASE-1 ENZYME
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